Venom peptides in association with standard drugs: a novel strategy for combating antibiotic resistance - an overview

Ashish K. Lamiyan Ramkesh Dalal Neelima R. Kumar About the authors

Abstract

Development of antibiotic resistance that leads to resurgence of bacterial infections poses a threat to disease-free existence for humankind and is a challenge for the welfare of the society at large. Despite research efforts directed towards treatment of pathogens, antibiotics within new improved classes have not emerged for years, a fact largely attributable to the pharmacological necessities compelling drug development. Recent reversion to the use of natural products alone or in combination with standard drugs has opened up new vistas for alternative therapeutics. The success of this strategy is evident in the sudden interest in plant extracts as additives/synergists for treatment of maladies caused by drug-resistant bacterial strains. Animal venoms have long fascinated scientists as sources of pharmacologically active components that can be exploited for the treatment of specific ailments and should be promoted further to clinical trials. In the present review, we outline the scope and possible methods for the applications of animal venoms in combination with commercial antibiotics to offer a better treatment approach against antibiotic-resistant infections.

Keywords:
Antibiotic resistance; Antimicrobials; Venom

Background

Antibiotics are the chemical entities that kill bacteria or slow down their growth. However, these one-time wonder medicines of the antibiotic era were not without serious side effects. It has now been established that long term use and overuse of antibiotics have given rise to a serious complication known as antimicrobial resistance [11. Ventola CL., therapeutics. The antibiotic resistance crisis: part 1: causes and threats. Pharm Ther. 2015 Apr;40(4):277-83.]. When penicillin, a naturally occurring antibiotic, was discovered in 1929 by Fleming, microbial-derived antibiotics brought a complete revolution in antimicrobial therapeutics and became the main line of defense against infectious diseases [11. Ventola CL., therapeutics. The antibiotic resistance crisis: part 1: causes and threats. Pharm Ther. 2015 Apr;40(4):277-83., 22. Chang HH, Cohen T, Grad YH, Hanage WP, O’Brien TF, Lipsitch M. Origin and proliferation of multiple-drug resistance in bacterial pathogens. Microbiol Mol Biol Rev. 2015 Mar;79(1):101-16.].

Despite recent advances in the field of modern medicine, bacteria still impose great risks to human health. Moreover, resistance emerged against many classes of commonly used antibiotics giving rise to multidrug resistance (MDR) [22. Chang HH, Cohen T, Grad YH, Hanage WP, O’Brien TF, Lipsitch M. Origin and proliferation of multiple-drug resistance in bacterial pathogens. Microbiol Mol Biol Rev. 2015 Mar;79(1):101-16.]. The unresolved status of resistance mechanisms has become such a matter of concern that the World Health Organization (WHO) considers it urgent to require the development of alternative therapeutics due to drug resistance.

Bacteria have been successful in developing resistance by means of different mechanisms including modification in their genes, an option for survival adopted by both pathogenic and non-pathogenic microorganisms [33. Fair RJ, Tor Y. Antibiotics and bacterial resistance in the 21st century. Perspect Medicin Chem. 2014 Aug 28;6:25-64.]. The high level of regular use and overuse of commercial antibiotics complicates the situation and hampers the effectiveness of drugs developed by the pharmaceutical industry [11. Ventola CL., therapeutics. The antibiotic resistance crisis: part 1: causes and threats. Pharm Ther. 2015 Apr;40(4):277-83.]. In the existing scenario, it is required to test the presently established line of drugs and work diligently to fill the gap between new drug discovery and the rising need for alternatives to combat antimicrobial resistance [44. Zaman SB, Hussain MA, Nye R, Mehta V, Mamun KT, Hossain NJC. A review on antibiotic resistance: alarm bells are ringing. Cureus. 2017 Jun 28;9(6):e1403.].

In the light of the fact that there was fast development of resistance against single-agent compounds (monotherapy) that target essential enzymes only, it was deemed urgent to develop antibiotics that act upon multiple targets. Then, two new classes of antibiotic agents entered the market in the last three decades, the oxazolidinones and lipopeptides [55. Silver LL. Multi-targeting by monotherapeutic antibacterials. Nat Rev Drug Discov. 2007 Jan;6(1):41-55.]. The development of the multitargeted antibiotics was due to the rise of resistance against the earlier ones such as sulfonamide drugs introduced in 1930s [66. van Miert AS. The sulfonamide-diaminopyrimidine story. J Vet Pharmacol Ther. 1994 Aug;17(4):309-16.].

The antibiotic resistance issue has propelled the examination of new alternative medications for bacterial infection control with synergistic effects [77. Gaynes RP. The discovery of penicillin-new insights after more than 75 years of clinical use. Emerg Infect Dis. 2017;23(5):849., 88. Tan SY, Tatsumura Y. Alexander Fleming (1881-1955): discoverer of penicillin. Singapore Med J. 2015 Jul;56(7):366-7.]. Since ancient times humankind has benefitted from natural products for antibiotic therapies [99. Lewis K. Antibiotics: Recover the lost art of drug discovery. Nature. 2012 May 23;485(7399):439-40.]. With the rapid increase in bacterial resistance against antibiotics, scientific efforts have been redirected towards a search for alternatives from nature that are potent but also less toxic. The present review focuses on antibiotic resistance, antimicrobial activity of animal venoms and strategies for the development of new first-line antibiotic therapies. In this context, animal venoms can be viewed, particularly in synergistic combinations, as a better option for rapidly developing a new line of antibiotics for combating pathogens resistant to conventional antibiotic therapeutics.

Methods

Search strategy

A systematic review was carried out following the rules and guidelines of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) [1010. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS One. 2009 Jul 21;6(7):e1000100.]. PubMed and Google Scholar were the electronic databases exclusively searched for articles published on antibiotic resistance and antimicrobials from venoms. No limit on publication dates was set. The literature search was initiated on March 1, 2019 with an update on September 30, 2019. The reference list of relevant articles was checked for additional titles for inclusion in the review. The literature was examined utilizing a search string containing combinations of terms including: “burden”, “antibiotic”, “antimicrobial”, “multi-drug”, “microbial-drug”, “resistance”, “gram-positive”, “gram-negative”, “venom”, “combination”, “additive” and “synergistic”.

Study selection

The studies were selected by the cooperation of two reviewers (AKL and RD) through the software Endnote (version X9, Clarivate Analytics, 2017) and verified by a third reviewer (NRK) ensuring the specificity and quality of the process. The literature was chosen on the basis of the following criteria: full-text accessible articles in which experimental studies were carried out; in an examination two antimicrobial peptides (AMPs), denominated La47 and Css54, from spider (Lachesana sp.) and scorpion (Centruroides suffusus), blends of La47 with the antibiotic agents like chloramphenicol, streptomycin and kanamycin, showed the best antimicrobial results. Likewise, the other novel peptide Css54 - when assessed with respect to antibiotic agents utilized for tuberculosis treatment, isoniazid, rifampicin, pyrazinamide and ethambutol - showed the best results with rifampicin [1111. Garcia F, Villegas E, Espino-Solis GP, Rodriguez A, Paniagua-Solis JF, Sandoval-Lopez G, et al. Antimicrobial peptides from arachnid venoms and their microbicidal activity in the presence of commercial antibiotics. J Antibiot (Tokyo). 2013 Jan;66(1):3-10.]. Another study reported an improvement against the bacterial growth (S. aureus and P. aeruginosa) when macropin was given in combination with commercial antibiotic at a lower dose as compared to the peptide or antibiotics used alone [1212. Owusu-Kwarteng J, Wuni A, Akabanda F, Tano-Debrah K, Jespersen LJBm. Prevalence, virulence factor genes and antibiotic resistance of Bacillus cereus sensu lato isolated from dairy farms and traditional dairy products. BMC Microbiol. 2017 Mar 14;17(1):65.]. Similarly, an additive effect was observed against P. aeruginosa strains treated with combinations of macropin and various antibiotics. The combination of oxacillin with macropin (for S. aureus) and piperacillin with macropin (for P. aeruginosa) increased the bacteriostasis rate very rapidly indicating a strong inhibitory potential [1313. Ko SJ, Kim MK, Bang JK, Seo CH, Luchian T, Park YJSr. Macropis fulvipes venom component Macropin exerts its antibacterial and anti-biofilm properties by damaging the plasma membranes of drug resistant bacteria. Sci Rep. 2017 Nov 29;7(1):16580.].

Data extraction

The literature for inclusion in the review was assessed by two independent reviewers (AKL and RD), who chose the studies based on the parameters required. The inclusion of articles was restricted to a very limited set of selected pathogens on the basis of drug resistance. The discussed sections included the action mechanism of the venom peptides with respect to membrane permeabilization and the lipopolysaccharide-binding phenomenon. The possibility of inconsistency was discussed by the contributing authors until reaching a final conclusion. The data extracted from the included articles contained the following: the author’s name and the year of publication; the type of disease; study design; random methods; treating method of antimicrobial involvement; treatment method and primary outcomes.

Results

Based on the selection process, out of the 327 total titles and abstracts retrieved over the specified search period, 123 studies were included in the final review (Fig. 1). Many of the studies included summaries of articles presented, experimental studies or review articles. The duplicate records and unrelated literature was excluded from the selection process. The PRISMA flowchart of the study plan is shown in Figure 1. The recorded data included author name, year of publication, country, type, sample size, bacterial species and drugs. The above details were extracted separately by two researchers (AKL and RD).

Figure 1.
PRISMA flowchart showing the study design process.

Mechanism of action for venoms

Venoms are complex chemical entities that comprise several components containing biologically active molecules. Snakes, scorpions, bees, wasps, centipedes and frogs are some animals that use venom for defending themselves or for capturing prey. These venoms or toxins, however, vary in composition and action mechanism from species to species. Certain peptides present in venom have been reported as being capable of causing damage to cellular membrane of microbes through electrostatic attraction forces [1414. Aslam B, Wang W, Arshad MI, Khurshid M, Muzammil S, Rasool MH, et al. Antibiotic resistance: a rundown of a global crisis. Infect Drug Resist. 2018 Oct 10;11:1645-58., 1515. Vasilchenko AS, Rogozhin EA. Sub-inhibitory effects of antimicrobial peptides. Front Microbiol. 2019;10:1160.]. The bacterial cell surfaces are generally negatively charged, a property solely responsible for the selective binding of AMPs with the bacterial cell membranes due to the presence of AMP-positive AA residues [1616. Malanovic N, Lohner K. Antimicrobial peptides targeting gram-positive bacteria. Pharmaceuticals (Basel). 2016 Sep;9(3):59.]. The mechanism of action of antimicrobial peptides (AMPs) derived from different animal venoms presents different working cascades. The difference in working mechanisms is due to factors including physiochemical properties of the peptides and composition of the lipids in membrane of the microbial pathogens [1717. Kumar P, Kizhakkedathu JN, Straus SK. Antimicrobial peptides: Diversity, mechanism of action and strategies to improve the activity and biocompatibility in vivo. Biomolecules. 2018 Jan 19;8(1):4.]. There are many mechanisms that explain how the pore formation processes cause expeditious disintegration of the bilayer structures present in cell membrane of a microbial pathogen [1818. Schmidt NW, Wong GCL. Antimicrobial peptides and induced membrane curvature: Geometry, coordination chemistry, and molecular engineering. Curr Opin Solid State Mater Sci. 2013 Aug;17(4):151-63.]. Previous studies have revealed the presence of complex hydrophobic proteins and peptides (myotoxic phospholipases, neurotoxins, latarcins) as secondary structures in forms such as a-helixes or b-sheets [1919. Borges RJ, Lemke N, Fontes MRM. PLA 2-like proteins myotoxic mechanism: a dynamic model description. Sci Rep. 2017;7(1):15514.]. It is highly essential to understand their key role in the crucial phenomenon of pore formation and membrane-degrading effects.

Membrane permeabilization

Several studies have been carried out on venom proteins and peptides isolated from snakes (reptiles) for exploring their antimicrobial activity. A study was carried out on CaTx-II, a type of phospholipase isolated from venom of the snake Crotalus adamanteus. It showed inhibition against Staphylococcus aureus at the concentration of 7.8 mg/ml, and against Bacillus pseudomallei and Enterobacter aerogenes at the concentration of 15.6 mg/ml. It was further reported that CaTx-II induced pore formation and membrane-damaging effects on the bacterial cell wall but caused no cytotoxicity to fibroblast cells isolated from skin and lung tissues [2020. Samy RP, Kandasamy M, Gopalakrishnakone P, Stiles BG, Rowan EG, Becker D, et al. Wound healing activity and mechanisms of action of an antibacterial protein from the venom of the eastern diamondback rattlesnake (Crotalus adamanteus). PLoS One. 2014 Feb 14;9(2):e80199.]. Furthermore, another peptide, Smp24, derived from the venom of the scorpion Maurus palmatus, which is usually 24 amino acids in length and carrying a triple positive charge, showed lethal potential against microbes. Smp24 also induced formation of pores with continuous increase in concentration and caused destruction of lipid bilayers, clearly indicating a phospholipid-dependent phenomenon [2121. Harrison PL, Heath GR, Johnson BR, Abdel-Rahman MA, Strong PN, Evans SD, et al. Phospholipid dependent mechanism of smp24, an α-helical antimicrobial peptide from scorpion venom. Biochim Biophys Acta. 2016 Nov;1858(11):2737-44.]. In addition, conotoxins, a type of amino acids rich in glycine and cysteine, have also been reported, thereby suggesting that the flexibility of structure in relation to aromatic residues and membrane interaction by hydrophobic attraction was due to the presence of these peptides. AMPs bearing positive charge/ net hydrophobic charges have flexible chain structures and are crucial for the development of inhibitory potential against pathogens [2222. Yang JL, Lu YA, Wu C, Tam JP. Antimicrobial and chemotactic activities of ω-conotoxin cyclic analogues. Peptides. 2001:487-8.].

Snake venom enzymes like PLA2-derived peptides resulted in permeabilization of the bacterial cell membrane, demonstrating that the peptides possessed bactericidal effects [2323. Oguiura N, Boni-Mitake M, Affonso R, Zhang G. In vitro antibacterial and hemolytic activities of crotamine, a small basic myotoxin from rattlesnake Crotalus durissus. J Antibiot (Tokyo). 2011 Mar 9;64(4):327-31.]. Simultaneously, these peptides blocked the effect of bacteria on macrophages and other target cells of the infected host by combining with bacterial lipopolysaccharides. Another study for understanding the mechanisms underlying the formation of pores by the venoms was performed on the sea anemone Stichodactyla healiantus with stychoysin I peptide (St-I) where the rate of permeabilization increased with the increment of sphingomyelin (SM) into phosphatidylcholine (PC), which was attributed to toxin binding [2424. Tejuca M, Dalla Serra M, Ferreras M, Lanio ME, Menestrina GJB. Mechanism of membrane permeabilization by sticholysin I, a cytolysin isolated from the venom of the sea anemone Stichodactyla helianthus. Biochemistry. 1996 Nov 26;35(47):14947-57.].

Binding to bacterial lipopolysaccharides (LPS)

Lipopolysaccharides (LPS) form an important constituent of the external membrane of Gram-negative bacteria and are functionally protective in nature. Due to this fact, the interaction of LPS with LPS-binding molecules attracts great attention in the development of antibiotics. An example of such an interaction is demonstrated by antimicrobial peptides (AMPs), which have a very high affinity for LPS in the bacterial membrane. The susceptibility of bacteria to the AMPs is confirmed by the biophysical properties of AMPs and their mode of interaction with LPS of the membrane [2525. Rosenfeld Y, Shai Y. Lipopolysaccharide (Endotoxin)-host defense antibacterial peptides interactions: role in bacterial resistance and prevention of sepsis. Biochim Biophys Acta. 2006 Sep;1758(9):1513-22.].

In recent studies, peptides derived from phospholipases (PLA2) from snake venom also revealed interaction with a specific lipid component of various Gram-negative bacteria leading to death of the pathogen [2626. Istivan TS, Coloe PJ. Phospholipase A in Gram-negative bacteria and its role in pathogenesis. Microbiology. 2006;152(5):1263-74.]. In another recent work, macropin was isolated from bee venom. Both Gram-positive and -negative bacteria exhibited inhibition by this antimicrobial component of the venom. Macropin was found to bind with the peptidoglycans and lipopolysaccharides and killed the bacteria by disruption in their membranes suggesting that it had antimicrobial potential and could be used as a bactericidal agent for infectious drug-resistant bacteria [2727. Monincová L, Veverka V, Slaninová J, Buděšínský M, Fučík V, Bednárová L, et al. Structure-activity study of macropin, a novel antimicrobial peptide from the venom of solitary bee Macropis fulvipes (Hymenoptera: Melittidae). J Pept Sci. 2014 Jun;20(6):375-84.]. Furthermore, the fractional inhibitory concentration index obtained in the experimental observations indicated that the component had additive and partially synergistic effects with conventional antibiotics against various drug-resistant bacteria [1313. Ko SJ, Kim MK, Bang JK, Seo CH, Luchian T, Park YJSr. Macropis fulvipes venom component Macropin exerts its antibacterial and anti-biofilm properties by damaging the plasma membranes of drug resistant bacteria. Sci Rep. 2017 Nov 29;7(1):16580.].

The phospholipases A2 (PLA2), i.e., myotoxins II (Lys49) and III (Asp49), isoforms isolated from the venom of Bothrops asper inflammatory fluids, revealed bactericidal potential. The study shown a higher binding affinity of the PLA2 isoforms to the isolated lipopolysaccharide (LPS) of susceptible bacteria [2828. Páramo L, Lomonte B, Pizarro-Cerdá J, Bengoechea JA, Gorvel JP, Moreno E. Bactericidal activity of Lys49 and Asp49 myotoxic phospholipases A2 from Bothrops asper snake venom--Synthetic Lys49 myotoxin II‐(115− 129)‐peptide identifies its bactericidal region. Eur J Biochem. 1998 Apr 15;253(2):452-61., 2929. Santamaría C, Larios S, Angulo Y, Pizarro-Cerda J, Gorvel JP, Moreno E, et al. Antimicrobial activity of myotoxic phospholipases A2 from crotalid snake venoms and synthetic peptide variants derived from their C-terminal region. Toxicon. 2005 Jun 1;45(7):807-15.]. Mastoparans (MPs) are one of the other antimicrobial peptides that are isolated from the wasp venom and show cationic and amphiphilic properties [3030. Konno K, Hisada M, Naoki H, Itagaki Y, Kawai N, Miwa A, et al. Structure and biological activities of eumenine mastoparan-AF (EMP-AF), a new mast cell degranulating peptide in the venom of the solitary wasp (Anterhynchium flavomarginatum micado). Toxicon. 2000 Nov 1;38(11):1505-15., 3131. Murata K, Shinada T, Ohfune Y, Hisada M, Yasuda A, Naoki H, et al. Novel mastoparan and protonectin analogs isolated from a solitary wasp, Orancistrocerus drewseni drewseni. Amino Acids. 2009 Jul;37(2):389-94.]. These balance different cell functions, including incitement of GTP-restricting protein, phospholipase C and can tie to a phospholipid bilayer [3030. Konno K, Hisada M, Naoki H, Itagaki Y, Kawai N, Miwa A, et al. Structure and biological activities of eumenine mastoparan-AF (EMP-AF), a new mast cell degranulating peptide in the venom of the solitary wasp (Anterhynchium flavomarginatum micado). Toxicon. 2000 Nov 1;38(11):1505-15.]. Mastoparan-1 (MP-1), another tetradecapeptide poison separated from hornet venom, was produced synthetically for an examination where Escherichia coli (E. coli 25922) and LPS were utilized for inducing sepsis in a murine model. It was discovered that MP-1 treatment at a rate of 3 mg/kg produced a defensive impact on mice from the general disease condition induced by the microscopic organisms and LPS challenges. MP-1 has antibacterial capacities against gram-negative and gram-positive bacteria, which may be due to the destructive action of the AMPs toward the bacterial membrane structure. In addition, respiratory burst inhibition was prominent during the treatment of murine peritoneal macrophages with MP-1 specifically. This effect could be attributed to the inhibition of NADPH oxidase in the film. Moreover, MP-1 additionally reduced the expression of TLR4, TNF-alpha and IL-6 mRNA and the formation of cytokines in LPS-administered murine peritoneal macrophages, thus demonstrating protective potential against deadly microorganisms revealing the bactericidal activity of AMPs, which limited the reactions of macrophages to the two microscopic organisms and LPS [3232. Yibin G, Jiang Z, Hong Z, Gengfa L, Liangxi W, Guo W, et al. A synthesized cationic tetradecapeptide from hornet venom kills bacteria and neutralizes lipopolysaccharide in vivo and in vitro. Biochem Pharmacol. 2005 Jul 15;70(2):209-19.].

Antibacterial peptides of venoms

The ability of venom proteins to bind to the lipid component of the cell membrane of several bacteria led to a series of extensive searches to isolate active proteins from animal poisons, which could be used alone or as additives and synergists with standard drugs in order to combat resistant bacteria. Some of the related studies that investigated the antibacterial peptides present in venom are displayed in Table 1.

Table 1.
Antibacterial peptides of venoms.

Combinational antimicrobial therapies

The potential of animal venoms against antimicrobial resistance has been intensively studied and proven highly effective. However, a combinational approach enables the option of a synergistic mode of action providing preferentially the most effective method for combating resistant bacteria. Enhancement in the activity of commercial antibiotics when administered in combination with venom peptides is already evidenced [1111. Garcia F, Villegas E, Espino-Solis GP, Rodriguez A, Paniagua-Solis JF, Sandoval-Lopez G, et al. Antimicrobial peptides from arachnid venoms and their microbicidal activity in the presence of commercial antibiotics. J Antibiot (Tokyo). 2013 Jan;66(1):3-10.]. Given that animal venoms themselves have been found to exhibit antibiotic properties against many antibiotic-resistant microbes, the potential can be utilized to repurpose commercial antibiotics in treatment of resistant pathogenic microorganisms. Combinational studies are being done in the hope of targeting the resistance mechanisms and getting a better response against the microbial pathogens, which is greater than the sum of their individual effects. Combination therapy is gaining attention over monotherapy from researchers across the globe for many of the life-threatening infectious diseases due to its ability to target multiple facets of a microbial infection [116116. Tyers M, Wright GD. Drug combinations: a strategy to extend the life of antibiotics in the 21st century. Nat Rev Microbiol. 2019 Mar;17(3):141-55.]. Antimicrobial-venom-based combination drugs can emerge as a research priority due to many advantages over synthetic drugs including rapid clinical usage, increased efficiency, need for lower doses, greater stability, and reduction in side effects as compared to those that arise from the use of commercial antibiotics. The mechanism underlying reduction in antibiotic resistance by different sources of animal venoms is still a puzzle that needs to be resolved. However, it is postulated in some studies that the venom extracts create channels through the plasma membranes of the microbes enabling the distortion of their intracellular components [117117. Carstens BB, Berecki G, Daniel JT, Lee HS, Jackson KA, Tae HS, et al. Structure-activity studies of Cysteine-Rich α-Conotoxins that inhibit high-voltage-activated calcium channels via GABAB receptor activation reveal a minimal functional motif. Angew Chem Int Ed Engl. 2016 Apr 4;55(15):4692-6., 118118. dos Santos Cabrera MP, Arcisio-Miranda M, Broggio Costa ST, Konno K, Ruggiero JR, Procopio J, et al. Study of the mechanism of action of anoplin, a helical antimicrobial decapeptide with ion channel-like activity, and the role of the amidated C-terminus. J Pept Sci. 2008 Jun;14(6):661-9.].

Synergism: bright side of antimicrobial studies

Many of the antibiotic combinations have been well studied and established for treatment of the resistant infections. It is inferred that in combination, one drug neutralizes the resistance mechanisms of the bacteria, and repurposes the other drug by increasing its efficacy [116116. Tyers M, Wright GD. Drug combinations: a strategy to extend the life of antibiotics in the 21st century. Nat Rev Microbiol. 2019 Mar;17(3):141-55.]. There are multiple pathways by which microbes have been successful in resisting antibiotic effects. The countable ones include target site modifications, use of MDR pumps and drug inactivation [119119. Chusri S, Villanueva I, Voravuthikunchai SP, Davies J. Enhancing antibiotic activity: a strategy to control Acinetobacter infections. J Antimicrob Chemother. 2009 Dec;64(6):1203-11.]. A complicated condition is seen when the microbe combines several of these approaches for their protection purpose [120120. Leclercq R. Mechanisms of resistance to macrolides and lincosamides: nature of the resistance elements and their clinical implications. Clin Infect Dis. 2002 Feb 15;34(4):482-92.]. The well-studied class of antibiotics like penicillin and chloramphenicol target the microbes by acting upon cell wall synthesis and inhibiting protein synthesis, respectively [121121. Kohanski MA, Dwyer DJ, Collins JJ. How antibiotics kill bacteria: from targets to networks. Nat Rev Microbiol. 2010 Jun;8(6):423-35.]. These antibiotics are currently facing resistance due to the fact that there are some integral proteins present in the outer cell membrane which act as checkpoints for the entry and exit of antibiotics; when these proteins are either lost or modified, permeability to the antibiotics is altered [120120. Leclercq R. Mechanisms of resistance to macrolides and lincosamides: nature of the resistance elements and their clinical implications. Clin Infect Dis. 2002 Feb 15;34(4):482-92.]. Many of the commercial antibiotics have become susceptible to these resistance mechanisms. In recent studies it has been reported that specific venom peptides are capable of inducing perturbations in the cell membranes thus allowing the permeability of antibiotics into bacterial cells [122122. Brogden KA. Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol. 2005;3(3):238-50., 123123. Yang L, Harroun TA, Weiss TM, Ding L, Huang H. Barrel-stave model or toroidal model? A case study on melittin pores. Biophys J. 2001;81(3):1475-85.].

Recent work on combination therapy

There are few works that depict the use of venoms in combination with the commercially used antibiotics showing increase in inhibitory activities. In an examination, two antimicrobial peptides (AMPs), denominated La47 and Css54, separated and filtered from the unrefined venom concentrate of spider (Lachesana sp.) and scorpion (Centruroides suffusus), were assessed in combination with the commercial antibiotics, chloramphenicol, ampicillin, novobiocin, streptomycin and kanamycin. Strikingly, blends of La47 with antibiotic agents such as chloramphenicol, streptomycin and kanamycin, showed the best antimicrobial results. Likewise, the other novel peptide Css54 when assessed with respect to antibiotic agents utilized for tuberculosis treatment, isoniazid, rifampicin, pyrazinamide and ethambutol, showed best results with rifampicin[1111. Garcia F, Villegas E, Espino-Solis GP, Rodriguez A, Paniagua-Solis JF, Sandoval-Lopez G, et al. Antimicrobial peptides from arachnid venoms and their microbicidal activity in the presence of commercial antibiotics. J Antibiot (Tokyo). 2013 Jan;66(1):3-10.]. In another study, two bacterial strains that were already resistant to antibiotics, i.e., S. aureus and P. aeruginosa, were used. There was an improvement observed against the bacterial growth when macropin was given in combination with commercial antibiotic. Combination therapy tried with macropin and antibiotic exhibited antibacterial potential at a lower dose as compared to the peptide or antibiotics used[1212. Owusu-Kwarteng J, Wuni A, Akabanda F, Tano-Debrah K, Jespersen LJBm. Prevalence, virulence factor genes and antibiotic resistance of Bacillus cereus sensu lato isolated from dairy farms and traditional dairy products. BMC Microbiol. 2017 Mar 14;17(1):65.] alone. The combination of macropin with gentamycin, tobramycin, ciprofloxacin, levofloxacin, piperacillin or oxacillin, was found to be very effective against the strains of S. aureus by inhibiting their growth. Similarly, an additive effect was produced against P. aeruginosa strains treated with combinations of macropin and various antibiotics. The combinations of oxacillin with macropin (for S. aureus) and piperacillin with macropin (for P. aeruginosa) increased the bacteriostasis rate very rapidly indicating a strong inhibitory potential [1313. Ko SJ, Kim MK, Bang JK, Seo CH, Luchian T, Park YJSr. Macropis fulvipes venom component Macropin exerts its antibacterial and anti-biofilm properties by damaging the plasma membranes of drug resistant bacteria. Sci Rep. 2017 Nov 29;7(1):16580.]. Overall, these data show a promising outlook for potential clinical treatments of bacterial infections using AMPs and commercial antibiotics. Furthermore, the research interest in venoms for their antibacterial potential has increased with time but no therapeutic approach has yet been achieved in the clinical trial phase.

Future

In recent times, modulating factors present in animal venoms have been improved with the help of advanced technologies and elucidated with respect to their potential in prevention or minimizing the toxic effects of microbial pathogens. It is believed that bacteria may develop resistance to an animal venom only if a specific target mechanism is involved, similarly to the monotherapy practices carried out in the case of present-day antibiotics. The probability of development of resistance decreases when a mixed array of mechanisms followed by the animal venoms are involved. Given the absence in the literature of any report on bacteria developing resistance against venoms, further research to explore the underlying mechanisms is required.

Until recently, the use of venom for clinical applications was hindered not only by low yield, but also by its complex composition, stability and toxicity aspect, which is still less explored. Given their emergence as significant and novel antimicrobial agents, animal venoms need to be investigated for improvement of treatment by combining these chemical entities with the conventional antibiotics. Enhanced durability, performance, strength, bioavailability can be obtained by the combinational therapeutic approach at the ground level.

Conclusion

The present situation of multidrug resistance is imposing a serious medical condition around the globe and is continuously augmenting the challenge faced by this line of research. The issue of commercial antibiotic use further becomes complicated due to the augmentation of both reduced efficacy and adverse side effects. This challenge prompted the researchers to seek venom-based antimicrobials as a solution against MDR as they are now known to play a vital role in the individual’s defense mechanism. Antimicrobial constituents, either alone or blended with commercial antibiotics, may prove to be an appropriate option for repurposing the antibiotics used earlier for treating the pathogens but which are ineffective today. The complex antimicrobial mechanism scheme of venoms reduces the defensive ability of bacteria, fungi and viruses and can prove to be helpful in treatment of diseases. The review explores the research in respect of the lethal potential of the venom and the other mechanisms by which animal venoms are able to combat resistance mechanisms. Our goal here was to propose an approach enabling assessment of the impact of combination therapy using a cocktail of animal venoms with the commercial antibiotics. In the literature, many studies have been located using venom for evaluation of their antibacterial potential, but no such studies have been found to date reporting any records of clinical trials. In conclusion, there is an urgent need to promote the venom peptides for clinical trials in order to evaluate their safety and efficacy for combatting resistance mechanisms.

Acknowledgments

The authors would like to thank Prof. Ram Kumar (Panjab University, Chandigarh) for their immense support and insightful suggestions during preparation of the manuscript. They are also thankful to Ms. Sapna Katnoria (Panjab University, Chandigarh) for the decision to publish and preparation of the paper.

References

  • 1. Ventola CL., therapeutics. The antibiotic resistance crisis: part 1: causes and threats. Pharm Ther. 2015 Apr;40(4):277-83.
  • 2. Chang HH, Cohen T, Grad YH, Hanage WP, O’Brien TF, Lipsitch M. Origin and proliferation of multiple-drug resistance in bacterial pathogens. Microbiol Mol Biol Rev. 2015 Mar;79(1):101-16.
  • 3. Fair RJ, Tor Y. Antibiotics and bacterial resistance in the 21st century. Perspect Medicin Chem. 2014 Aug 28;6:25-64.
  • 4. Zaman SB, Hussain MA, Nye R, Mehta V, Mamun KT, Hossain NJC. A review on antibiotic resistance: alarm bells are ringing. Cureus. 2017 Jun 28;9(6):e1403.
  • 5. Silver LL. Multi-targeting by monotherapeutic antibacterials. Nat Rev Drug Discov. 2007 Jan;6(1):41-55.
  • 6. van Miert AS. The sulfonamide-diaminopyrimidine story. J Vet Pharmacol Ther. 1994 Aug;17(4):309-16.
  • 7. Gaynes RP. The discovery of penicillin-new insights after more than 75 years of clinical use. Emerg Infect Dis. 2017;23(5):849.
  • 8. Tan SY, Tatsumura Y. Alexander Fleming (1881-1955): discoverer of penicillin. Singapore Med J. 2015 Jul;56(7):366-7.
  • 9. Lewis K. Antibiotics: Recover the lost art of drug discovery. Nature. 2012 May 23;485(7399):439-40.
  • 10. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS One. 2009 Jul 21;6(7):e1000100.
  • 11. Garcia F, Villegas E, Espino-Solis GP, Rodriguez A, Paniagua-Solis JF, Sandoval-Lopez G, et al. Antimicrobial peptides from arachnid venoms and their microbicidal activity in the presence of commercial antibiotics. J Antibiot (Tokyo). 2013 Jan;66(1):3-10.
  • 12. Owusu-Kwarteng J, Wuni A, Akabanda F, Tano-Debrah K, Jespersen LJBm. Prevalence, virulence factor genes and antibiotic resistance of Bacillus cereus sensu lato isolated from dairy farms and traditional dairy products. BMC Microbiol. 2017 Mar 14;17(1):65.
  • 13. Ko SJ, Kim MK, Bang JK, Seo CH, Luchian T, Park YJSr. Macropis fulvipes venom component Macropin exerts its antibacterial and anti-biofilm properties by damaging the plasma membranes of drug resistant bacteria. Sci Rep. 2017 Nov 29;7(1):16580.
  • 14. Aslam B, Wang W, Arshad MI, Khurshid M, Muzammil S, Rasool MH, et al. Antibiotic resistance: a rundown of a global crisis. Infect Drug Resist. 2018 Oct 10;11:1645-58.
  • 15. Vasilchenko AS, Rogozhin EA. Sub-inhibitory effects of antimicrobial peptides. Front Microbiol. 2019;10:1160.
  • 16. Malanovic N, Lohner K. Antimicrobial peptides targeting gram-positive bacteria. Pharmaceuticals (Basel). 2016 Sep;9(3):59.
  • 17. Kumar P, Kizhakkedathu JN, Straus SK. Antimicrobial peptides: Diversity, mechanism of action and strategies to improve the activity and biocompatibility in vivo Biomolecules. 2018 Jan 19;8(1):4.
  • 18. Schmidt NW, Wong GCL. Antimicrobial peptides and induced membrane curvature: Geometry, coordination chemistry, and molecular engineering. Curr Opin Solid State Mater Sci. 2013 Aug;17(4):151-63.
  • 19. Borges RJ, Lemke N, Fontes MRM. PLA 2-like proteins myotoxic mechanism: a dynamic model description. Sci Rep. 2017;7(1):15514.
  • 20. Samy RP, Kandasamy M, Gopalakrishnakone P, Stiles BG, Rowan EG, Becker D, et al. Wound healing activity and mechanisms of action of an antibacterial protein from the venom of the eastern diamondback rattlesnake (Crotalus adamanteus). PLoS One. 2014 Feb 14;9(2):e80199.
  • 21. Harrison PL, Heath GR, Johnson BR, Abdel-Rahman MA, Strong PN, Evans SD, et al. Phospholipid dependent mechanism of smp24, an α-helical antimicrobial peptide from scorpion venom. Biochim Biophys Acta. 2016 Nov;1858(11):2737-44.
  • 22. Yang JL, Lu YA, Wu C, Tam JP. Antimicrobial and chemotactic activities of ω-conotoxin cyclic analogues. Peptides. 2001:487-8.
  • 23. Oguiura N, Boni-Mitake M, Affonso R, Zhang G. In vitro antibacterial and hemolytic activities of crotamine, a small basic myotoxin from rattlesnake Crotalus durissus J Antibiot (Tokyo). 2011 Mar 9;64(4):327-31.
  • 24. Tejuca M, Dalla Serra M, Ferreras M, Lanio ME, Menestrina GJB. Mechanism of membrane permeabilization by sticholysin I, a cytolysin isolated from the venom of the sea anemone Stichodactyla helianthus Biochemistry. 1996 Nov 26;35(47):14947-57.
  • 25. Rosenfeld Y, Shai Y. Lipopolysaccharide (Endotoxin)-host defense antibacterial peptides interactions: role in bacterial resistance and prevention of sepsis. Biochim Biophys Acta. 2006 Sep;1758(9):1513-22.
  • 26. Istivan TS, Coloe PJ. Phospholipase A in Gram-negative bacteria and its role in pathogenesis. Microbiology. 2006;152(5):1263-74.
  • 27. Monincová L, Veverka V, Slaninová J, Buděšínský M, Fučík V, Bednárová L, et al. Structure-activity study of macropin, a novel antimicrobial peptide from the venom of solitary bee Macropis fulvipes (Hymenoptera: Melittidae). J Pept Sci. 2014 Jun;20(6):375-84.
  • 28. Páramo L, Lomonte B, Pizarro-Cerdá J, Bengoechea JA, Gorvel JP, Moreno E. Bactericidal activity of Lys49 and Asp49 myotoxic phospholipases A2 from Bothrops asper snake venom--Synthetic Lys49 myotoxin II‐(115− 129)‐peptide identifies its bactericidal region. Eur J Biochem. 1998 Apr 15;253(2):452-61.
  • 29. Santamaría C, Larios S, Angulo Y, Pizarro-Cerda J, Gorvel JP, Moreno E, et al. Antimicrobial activity of myotoxic phospholipases A2 from crotalid snake venoms and synthetic peptide variants derived from their C-terminal region. Toxicon. 2005 Jun 1;45(7):807-15.
  • 30. Konno K, Hisada M, Naoki H, Itagaki Y, Kawai N, Miwa A, et al. Structure and biological activities of eumenine mastoparan-AF (EMP-AF), a new mast cell degranulating peptide in the venom of the solitary wasp (Anterhynchium flavomarginatum micado). Toxicon. 2000 Nov 1;38(11):1505-15.
  • 31. Murata K, Shinada T, Ohfune Y, Hisada M, Yasuda A, Naoki H, et al. Novel mastoparan and protonectin analogs isolated from a solitary wasp, Orancistrocerus drewseni drewseni Amino Acids. 2009 Jul;37(2):389-94.
  • 32. Yibin G, Jiang Z, Hong Z, Gengfa L, Liangxi W, Guo W, et al. A synthesized cationic tetradecapeptide from hornet venom kills bacteria and neutralizes lipopolysaccharide in vivo and in vitro Biochem Pharmacol. 2005 Jul 15;70(2):209-19.
  • 33. Long SS, Pickering LK, Prober CG. Principles and practice of pediatric infectious disease: Elsevier Health Sciences; 2012.
  • 34. Orivel J, Redeker V, Le Caer JP, Krier F, Revol-Junelles AM, Longeon A, et al. Ponericins, new antibacterial and insecticidal peptides from the venom of the ant Pachycondyla goeldii J Biol Chem. 2001 May 25;276(21):17823-9.
  • 35. Chen LK, Kuo SC, Chang KC, Cheng CC, Yu PY, Chang CH, et al. Clinical antibiotic-resistant Acinetobacter baumannii strains with higher susceptibility to environmental phages than antibiotic-sensitive strains. Sci Rep. 2017 Jul 24;7(1):6319.
  • 36. Falcao C, de La Torre B, Pérez-Peinado C, Barron A, Andreu D, Rádis-Baptista G. Vipericidins: a novel family of cathelicidin-related peptides from the venom gland of South American pit vipers. Amino Acids. 2014 Nov;46(11):2561-71.
  • 37. Park NG, Yamato Y, Lee S, Sugihara G. Interaction of mastoparan-B from venom of a hornet in Taiwan with phospholipid bilayers and its antimicrobial activity. Biopolymers. 1995 Dec;36(6):793-801.
  • 38. Vila-Farres X, De La Maria CG, López-Rojas R, Pachón J, Giralt E, Vila J. In vitro activity of several antimicrobial peptides against colistin-susceptible and colistin-resistant Acinetobacter baumannii Clin Microbiol Infect. 2012 Apr;18(4):383-7.
  • 39. Wang Y, Wang L, Yang H, Xiao H, Farooq A, Liu Z, et al. The spider venom peptide lycosin-II has potent antimicrobial activity against clinically isolated bacteria. Toxins (Basel). 2016 Apr 26;8(5):119.
  • 40. Zhao F, Lan XQ, Du Y, Chen PY, Zhao J, Zhao F, et al. King cobra peptide OH-CATH30 as a potential candidate drug through clinic drug-resistant isolates. Zool Res. 2018 Mar 18;39(2):87-96.
  • 41. Čeřovský V, Hovorka O, Cvačka J, Voburka Z, Bednárová L, Borovičková L, et al. Melectin: a novel antimicrobial peptide from the venom of the cleptoparasitic bee Melecta albifrons Chembiochem. 2008 Nov 24;9(17):2815-21.
  • 42. de Souza BM, da Silva AVR, Resende VMF, Arcuri HA, dos Santos Cabrera MP, Ruggiero Neto, J, et al. Characterization of two novel polyfunctional mastoparan peptides from the venom of the social wasp Polybia paulista Peptides. 2009 Aug;30(8):1387-95.
  • 43. Ye J, Zhao H, Wang H, Bian J, Zheng R. A defensin antimicrobial peptide from the venoms of Nasonia vitripennis Toxicon. 2010 Aug 1;56(1):101-6.
  • 44. Bacha AB, Alonazi MA, Elshikh MS, Karray A. A novel bactericidal homodimeric PLA2 group-I from Walterinnesia aegyptia venom. Int J Biol Macromol. 2018 Oct 1;117:1140-6.
  • 45. Mazza P, Zani F, Martelli P. Studies on the antibiotic resistance of Bacillus subtilis strains used in oral bacteriotherapy. Boll Chim Farm. 1992 Dec;131(11):401-8.
  • 46. Pluzhnikov KA, Kozlov SA, Vassilevski AA, Vorontsova OV, Feofanov AV, Grishin EV. Linear antimicrobial peptides from Ectatomma quadridens ant venom. Biochimie. 2014 Dec;107:211-5.
  • 47. Čeřovský V, Buděšínský M, Hovorka O, Cvačka J, Voburka Z, Slaninová J, et al. Lasioglossins: three novel antimicrobial peptides from the venom of the eusocial bee Lasioglossum laticeps (Hymenoptera: Halictidae). Chembiochem. 2009 Aug 17;10(12):2089-99.
  • 48. Monincová L, Buděšínský M, Slaninová J, Hovorka O, Cvačka J, Voburka Z, et al. Novel antimicrobial peptides from the venom of the eusocial bee Halictus sexcinctus (Hymenoptera: Halictidae) and their analogs. Amino Acids. 2010 Aug;39(3):763-75.
  • 49. Monincová L, Slaninová J, Fučík V, Hovorka O, Voburka Z, Bednárová L, et al. Lasiocepsin, a novel cyclic antimicrobial peptide from the venom of eusocial bee Lasioglossum laticeps (Hymenoptera: Halictidae). Amino Acids. 2012 Aug;43(2):751-61.
  • 50. Čujová S, Slaninová J, Monincová L, Fučík V, Bednárová L, Štokrová J, et al. Panurgines, novel antimicrobial peptides from the venom of communal bee Panurgus calcaratus (Hymenoptera: Andrenidae). Amino Acids. 2013 Jul;45(1):143-57.
  • 51. Čujová S, Bednárová L, Slaninová J, Straka J, Čeřovský V. Interaction of a novel antimicrobial peptide isolated from the venom of solitary bee Colletes daviesanus with phospholipid vesicles and Escherichia coli cells. J Pept Sci. 2014 Nov;20(11):885-95.
  • 52. Zhu S, Tytgat J. The scorpine family of defensins: gene structure, alternative polyadenylation and fold recognition. Cell Mol Life Sci. 2004 Jul;61(14):1751-63.
  • 53. Uawonggul N, Thammasirirak S, Chaveerach A, Arkaravichien T, Bunyatratchata W, Ruangjirachuporn W, et al. Purification and characterization of Heteroscorpine-1 (HS-1) toxin from Heterometrus laoticus scorpion venom. Toxicon. 2007 Jan;49(1):19-29.
  • 54. Díaz P, D’Suze G, Salazar V, Sevcik C, Shannon JD, Sherman NE, et al. Antibacterial activity of six novel peptides from Tityus discrepans scorpion venom. A fluorescent probe study of microbial membrane Na+ permeability changes. Toxicon. 2009 Nov;54(6):802-17.
  • 55. Moerman L, Bosteels S, Noppe W, Willems J, Clynen E, Schoofs L, et al. Antibacterial and antifungal properties of α-helical, cationic peptides in the venom of scorpions from southern Africa. Eur J Biochem. 2002 Oct;269(19):4799-810.
  • 56. Torres-Larios A, Gurrola GB, Zamudio FZ, Possani LD. Hadrurin, a new antimicrobial peptide from the venom of the scorpion Hadrurus aztecus Eur J Biochem. 2000 Aug;267(16):5023-31.
  • 57. Corzo G, Escoubas P, Villegas E, Barnham KJ, He W, Norton RS, et al. Characterization of unique amphipathic antimicrobial peptides from venom of the scorpion Pandinus imperator Biochem J. 2001 Oct;359(Pt 1):35-45.
  • 58. Dai C, Ma Y, Zhao Z, Zhao R, Wang Q, Wu Y, et al. Mucroporin, the first cationic host defense peptide from the venom of Lychas mucronatus Antimicrob Agents Chemother. 2008 Nov;52(11):3967-72.
  • 59. Zhao Z, Ma Y, Dai C, Zhao R, Li S, Wu Y, et al. Imcroporin, a new cationic antimicrobial peptide from the venom of the scorpion Isometrus maculates Antimicrob Agents Chemother. 2009 Aug;53(8):3472-7.
  • 60. Budnik BA, Olsen J, Egorov T, Anisimova V, Galkina T, Musolyamov A, et al. De novo sequencing of antimicrobial peptides isolated from the venom glands of the wolf spider Lycosa singoriensis J Mass Spectrom. 2004 Feb;39(2):193-201.
  • 61. Kozlov SA, Vassilevski AA, Feofanov AV, Surovoy AY, Karpunin DV, Grishin EV. Latarcins, antimicrobial and cytolytic peptides from the venom of the spider Lachesana tarabaevi (Zodariidae) that exemplify biomolecular diversity. J Biol Chem. 2006 Jul 28;281(30):20983-92.
  • 62. Lazarev VN, Polina NF, Shkarupeta MM, Kostrjukova ES, Vassilevski AA, Kozlov SA, et al. Spider venom peptides for gene therapy of Chlamydia infection. Antimicrob Agents Chemother. 2011 Nov;55(11):5367-9.
  • 63. Vassilevski AA, Kozlov SA, Samsonova OV, Egorova NS, Karpunin DV, Pluzhnikov KA, et al. Cyto-insectotoxins, a novel class of cytolytic and insecticidal peptides from spider venom. Biochem J. 2008 May;411(3):687-96.
  • 64. Kuzmenkov AI, Fedorova IM, Vassilevski AA, Grishin EV. Cysteine-rich toxins from Lachesana tarabaevi spider venom with amphiphilic C-terminal segments. ScienceDirect. 2013 Feb;1828(2):724-31.
  • 65. Mendes MA, de Souza BM, Marques MR, Palma MS. Structural and biological characterization of two novel peptides from the venom of the neotropical social wasp Agelaia pallipes pallipes Toxicon. 2004 Jul;44(1):67-74.
  • 66. Wang K, Yan J, Chen R, Dang W, Zhang B, Zhang W, et al. Membrane-active action mode of polybia-CP, a novel antimicrobial peptide isolated from the venom of Polybia paulista Antimicrob Agents Chemother. 2012 Jun;56(6):3318-23.
  • 67. Konno K, Hisada M, Fontana R, Lorenzi CC, Naoki H, Itagaki Y, et al. Anoplin, a novel antimicrobial peptide from the venom of the solitary wasp Anoplius samariensis Biochim Biophys Acta. 2001 Nov 26;1550(1):70-80.
  • 68. Konno K, Hisada M, Naoki H, Itagaki Y, Fontana R, Rangel M, et al. Eumenitin, a novel antimicrobial peptide from the venom of the solitary eumenine wasp Eumenes rubronotatus Peptides. 2006 Nov;27(11):2624-31.
  • 69. Konno K, Rangel M, Oliveira JS, dos Santos Cabrera MP, Fontana R, Hirata IY, et al. Decoralin, a novel linear cationic α-helical peptide from the venom of the solitary eumenine wasp Oreumenes decoratus Peptides. 2007 Dec;28(12):2320-7.
  • 70. Krishnakumari V, Nagaraj R. Antimicrobial and hemolytic activities of crabrolin, a 13-residue peptide from the venom of the European hornet, Vespa crabro, and its analogs. J Pept Res. 1997 Aug;50(2):88-93.
  • 71. Bautista JR, Teves F. Antibiotic susceptibility testing of isolated Bacillus thuringiensis from three soil types around Iligan City, Philippines. African J Microbiol Res. 2013 Feb;7(8):678-82.
  • 72. Yan L, Adams ME. Lycotoxins, antimicrobial peptides from venom of the wolf spider Lycosa carolinensis J Biol Chem. 1998;273(4):2059-66.
  • 73. Zelezetsky I, Pag U, Antcheva N, Sahl HG, Tossi A. Identification and optimization of an antimicrobial peptide from the ant venom toxin pilosulin. Arch Biochem Biophys. 2005 Feb 15;434(2):358-64.
  • 74. Liu L, Chen D, Liu L, Lan R, Hao S, Jin W, et al. Genetic diversity, multidrug resistance, and virulence of Citrobacter freundii from diarrheal patients and healthy individuals. Front Cell Infect Microbiol. 2018 Jul 10;8:233.
  • 75. Fennell JF, Shipman WH, Cole LJ. Antibacterial action of a bee venom fraction (melittin) against a penicillin-resistant staphylococcus and other microorganisms. Res Dev Tech Rep. 1967 Dec 5:1-13.
  • 76. Wachinger M, Kleinschmidt A, Winder D, von Pechmann N, Ludvigsen A, Neumann M, et al. Antimicrobial peptides melittin and cecropin inhibit replication of human immunodeficiency virus 1 by suppressing viral gene expression. J Gen Virol. 1998 Apr;79(Pt 4):731-40.
  • 77. Carter V, Underhill A, Baber I, Sylla L, Baby M, Larget-Thiery I, et al. Killer bee molecules: antimicrobial peptides as effector molecules to target sporogonic stages of Plasmodium. PLoS Pathog. 2013;9(11):e1003790.
  • 78. Alia O, Laila M, Antonious A. Antimicrobial effect of melittin isolated from Syrian honeybee (Apis mellifera) venom and its wound healing potential. ResearchGate. 2013 Aug;21:318-24.
  • 79. Leandro LF, Mendes CA, Casemiro LA, Vinholis AH, Cunha WR, Almeida R, et al. Antimicrobial activity of apitoxin, melittin and phospholipase A2 of honey bee (Apis mellifera) venom against oral pathogens. An Acad Bras Ciênc. 2015 Mar;87(1):147-55.
  • 80. Matanic VCA, Castilla V. Antiviral activity of antimicrobial cationic peptides against Junin virus and herpes simplex virus. Int J Antimicrob Agents. 2004 May;23(4):382-9.
  • 81. Davin-Regli A, Pages JM. Enterobacter aerogenes and Enterobacter cloacae; versatile bacterial pathogens confronting antibiotic treatment. Front Microbiol. 2015 May 18;6:392.
  • 82. Hernández-Aponte CA, Silva-Sanchez J, Quintero-Hernández V, Rodríguez-Romero A, Balderas C, Possani LD, et al. Vejovine, a new antibiotic from the scorpion venom of Vaejovis mexicanus Toxicon. 2011 Jan;57(1):84-92.
  • 83. Wu S, Nie Y, Zeng XC, Cao H, Zhang L, Zhou L, et al. Genomic and functional characterization of three new venom peptides from the scorpion Heterometrus spinifer Peptides. 2014 Mar;53:30-41.
  • 84. Yang X, Wang Y, Lee WH, Zhang Y. Antimicrobial peptides from the venom gland of the social wasp Vespa tropica Toxicon. 2013 Nov;74:151-7.
  • 85. Almaaytah A, Tarazi S, Alsheyab F, Al-Balas Q, Mukattash T. Antimicrobial and antibiofilm activity of mauriporin, a multifunctional scorpion venom peptide. Int J Pept Res Ther. 2014 Apr 1;20(4):397-408.
  • 86. Rasheed MU, Thajuddin N, Ahamed P, Teklemariam Z, Jamil K. Antimicrobial drug resistance in strains of Escherichia coli isolated from food sources. Rev Inst Med Trop Sao Paulo. 2014 Jul-Aug;56(4):341-6.
  • 87. Peng K, Kong Y, Zhai L, Wu X, Jia P, Liu J, et al. Two novel antimicrobial peptides from centipede venoms. Toxicon. 2010 Feb-Mar;55(2-3):274-9.
  • 88. Biggs JS, Rosenfeld Y, Shai Y, Olivera BJB. Conolysin-Mt: a conus peptide that disrupts cellular membranes. Biochemistry. 2007 Nov 6;46(44):12586-93.
  • 89. Gao B, Sherman P, Luo L, Bowie J, Zhu S. Structural and functional characterization of two genetically related meucin peptides highlights evolutionary divergence and convergence in antimicrobial peptides. Faseb J. 2009 Apr;23(4):1230-45.
  • 90. Santamaría C, Larios S, Quirós S, Pizarro-Cerda J, Gorvel JP, Lomonte B, et al. Bactericidal and antiendotoxic properties of short cationic peptides derived from a snake venom Lys49 phospholipase A2. Antimicrob Agents Chemother. 2005 Apr;49(4):1340-5.
  • 91. Fan Z, Cao L, He Y, Hu J, Di Z, Wu Y, et al. Ctriporin, a new anti-methicillin-resistant Staphylococcus aureus peptide from the venom of the scorpion Chaerilus tricostatus Antimicrob Agents Chemother. 2011 Nov;55(11):5220-9.
  • 92. Zeng XC, Zhou L, Shi W, Luo X, Zhang L, Nie Y, et al. Three new antimicrobial peptides from the scorpion Pandinus imperator Peptides. 2013 Jul;45:28-34.
  • 93. de Melo ET, Estrela AB, Santos ECG, Machado PRL, Farias KJS, Torres TM, et al. Structural characterization of a novel peptide with antimicrobial activity from the venom gland of the scorpion Tityus stigmurus: Stigmurin. Peptides. 2015 Jun;68:3-10.
  • 94. Henriksen JR, Etzerodt T, Gjetting T, Andresen TL. Side chain hydrophobicity modulates therapeutic activity and membrane selectivity of antimicrobial peptide mastoparan-X. PLoS One. 2014 Mar 12;9(3):e91007.
  • 95. Chen LW, Kao PH, Fu YS, Lin SR, Chang LS. Membrane-damaging activity of Taiwan cobra cardiotoxin 3 is responsible for its bactericidal activity. Toxicon. 2011 Jul;58(1):46-53.
  • 96. Sala A, Cabassi CS, Santospirito D, Polverini E, Flisi S, Cavirani S, et al. Novel Naja atra cardiotoxin 1 (CTX-1) derived antimicrobial peptides with broad spectrum activity. PLoS One. 2018;13(1).
  • 97. Golob M, Pate M, Kušar D, Dermota U, Avberšek J, Papić B, et al. Antimicrobial resistance and virulence genes in Enterococcus faecium and Enterococcus faecalis from humans and retail red meat. Biomed Res Int. 2019 May 9;2019.
  • 98. Bae S, Lee J, Lee J, Kim E, Lee S, Yu J, et al. Antimicrobial resistance in Haemophilus influenzae respiratory tract isolates in Korea: results of a nationwide acute respiratory infections surveillance. Antimicrob Agents Chemother. 2010 Jan;54(1):65-71.
  • 99. Sanchez GV, Master RN, Clark RB, Fyyaz M, Duvvuri P, Ekta G, et al. Klebsiella pneumoniae antimicrobial drug resistance, United States, 1998-2010. Emerg Infect Dis. 2013 Jan;19(1):133-6.
  • 100. Yayan J, Ghebremedhin B, Rasche K. Antibiotic resistance of Pseudomonas aeruginosa in pneumonia at a single university hospital center in Germany over a 10-year period. PLoS One. 2015 Oct 2;10(10):e0139836.
  • 101. Diniz-Sousa R, Caldeira CA, Kayano AM, Paloschi MV, Pimenta DC, Simões-Silva R, et al. Identification of the molecular determinants of the antibacterial activity of Lmut TX, a Lys49 phospholipase A2 homologue isolated from Lachesis muta muta snake venom (Linnaeus, 1766). Basic Clin Pharmacol Toxicol. 2018 Apr;122(4):413-23.
  • 102. Kittinger C, Lipp M, Baumert R, Folli B, Koraimann G, Toplitsch D, et al. Antibiotic resistance patterns of Pseudomonas spp. isolated from the river Danube. Front Microbiol. 2016 May 3;7:586.
  • 103. Molina L, Udaondo Z, Duque E, Fernández M, Molina-Santiago C, Roca A, et al. Antibiotic resistance determinants in a Pseudomonas putida strain isolated from a hospital. PLoS One. 2014;9(1):e81604.
  • 104. Lowy FD. Antimicrobial resistance: the example of Staphylococcus aureus J Clin Invest. 2003 May 1;111(9):1265-73.
  • 105. Vargas LJ, Londoño M, Quintana JC, Rua C, Segura C, Lomonte B, et al. An acidic phospholipase A2 with antibacterial activity from Porthidium nasutum snake venom. Comp Biochem Physiol B Biochem Mol Biol. 2012 Apr;161(4):341-7.
  • 106. Klemm EJ, Shakoor S, Page AJ, Qamar FN, Judge K, Saeed DK, et al. Emergence of an extensively drug-resistant Salmonella enterica serovar Typhi clone harboring a promiscuous plasmid encoding resistance to fluoroquinolones and third-generation cephalosporins. mBio. 2018 Feb 20;9(1):e00105-18.
  • 107. Archer GL, Tenenbaum MJ. Antibiotic-resistant Staphylococcus epidermidis in patients undergoing cardiac surgery. Antimicrob Agents Chemother. 1980 Feb;17(2):269-72.
  • 108. Chu YW, Houang ET, Lyon DJ, Ling JM, Ng TKk, Cheng AF. Antimicrobial resistance in Shigella flexneri and Shigella sonnei in Hong Kong, 1986 to 1995. Antimicrob Agents Chemother. 1998 Feb;42(2):440-3.
  • 109. Stock I, Grueger T, Wiedemann B. Natural antibiotic susceptibility of strains of Serratia marcescens and the S. liquefaciens complex: S. liquefaciens sensu stricto, S. proteamaculans and S. grimesii Int J Antimicrob Agents. 2003 Jul;22(1):35-47.
  • 110. Cherazard R, Epstein M, Doan TL, Salim T, Bharti S, Smith MA. Antimicrobial resistant Streptococcus pneumoniae: prevalence, mechanisms, and clinical implications. Am J Ther. 2017 May;24(3):e361-e9.
  • 111. Arvand M, Hoeck M, Hahn H, Wagner J. Antimicrobial resistance in Streptococcus pyogenes isolates in Berlin. J Antimicrob Chemother. 2000 Oct;46(4):621-4.
  • 112. Erickson PR, Herzberg MC. Emergence of antibiotic resistant Streptococcus sanguis in dental plaque of children after frequent antibiotic therapy. Pediatr Dent. 1999 May-Jun;21:181-5.
  • 113. Tadesse DA, Singh A, Zhao S, Bartholomew M, Womack N, Ayers S, et al. Antimicrobial resistance in Salmonella in the United States from 1948 to 1995. Antimicrob Agents Chemother. 2016 Mar 25;60(4):2567-71.
  • 114. Dookie N, Rambaran S, Padayatchi N, Mahomed S, Naidoo K. Evolution of drug resistance in Mycobacterium tuberculosis: a review on the molecular determinants of resistance and implications for personalized care. J Antimicrob Chemother. 2018 May 1;73(5):1138-51.
  • 115. Ramírez-Carreto S, Jiménez-Vargas JM, Rivas-Santiago B, Corzo G, Possani LD, Becerril B, et al. Peptides from the scorpion Vaejovis punctatus with broad antimicrobial activity. Peptides. 2015 Nov;73:51-9.
  • 116. Tyers M, Wright GD. Drug combinations: a strategy to extend the life of antibiotics in the 21st century. Nat Rev Microbiol. 2019 Mar;17(3):141-55.
  • 117. Carstens BB, Berecki G, Daniel JT, Lee HS, Jackson KA, Tae HS, et al. Structure-activity studies of Cysteine-Rich α-Conotoxins that inhibit high-voltage-activated calcium channels via GABAB receptor activation reveal a minimal functional motif. Angew Chem Int Ed Engl. 2016 Apr 4;55(15):4692-6.
  • 118. dos Santos Cabrera MP, Arcisio-Miranda M, Broggio Costa ST, Konno K, Ruggiero JR, Procopio J, et al. Study of the mechanism of action of anoplin, a helical antimicrobial decapeptide with ion channel-like activity, and the role of the amidated C-terminus. J Pept Sci. 2008 Jun;14(6):661-9.
  • 119. Chusri S, Villanueva I, Voravuthikunchai SP, Davies J. Enhancing antibiotic activity: a strategy to control Acinetobacter infections. J Antimicrob Chemother. 2009 Dec;64(6):1203-11.
  • 120. Leclercq R. Mechanisms of resistance to macrolides and lincosamides: nature of the resistance elements and their clinical implications. Clin Infect Dis. 2002 Feb 15;34(4):482-92.
  • 121. Kohanski MA, Dwyer DJ, Collins JJ. How antibiotics kill bacteria: from targets to networks. Nat Rev Microbiol. 2010 Jun;8(6):423-35.
  • 122. Brogden KA. Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol. 2005;3(3):238-50.
  • 123. Yang L, Harroun TA, Weiss TM, Ding L, Huang H. Barrel-stave model or toroidal model? A case study on melittin pores. Biophys J. 2001;81(3):1475-85.

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Publication Dates

  • Publication in this collection
    10 Aug 2020
  • Date of issue
    2020

History

  • Received
    03 Feb 2020
  • Accepted
    08 July 2020
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