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Livestock Diseases • Pesq. Vet. Bras. 41 • 2021 • https://doi.org/10.1590/1678-5150-PVB-6862   copy

Antimicrobial properties of heterocyclic compounds against clinical mastitis isolates

Propriedades antimicrobianas de compostos heterocíclicos contra isolados de mastite clínica

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT:

Mastitis causes significant economic losses to the dairy cattle industry. The present study aimed to evaluate the antibacterial properties of 39 heterocyclic derivatives (1,3-thiazoles and 4-thiazolidinones) against clinical mastitis isolates from dairy cows. Milk samples were collected from cows with clinical mastitis and the bacterial species were identified by PCR. Antibacterial activity was assessed using the broth microdilution method. First, 39 heterocyclic compounds were tested against four bacterial isolates (Staphylococcus aureus, Streptococcus agalactiae, Corynebacterium bovis and Escherichia coli) randomly chosen from those recovered from the milk samples (Study 1). Subsequently, the compounds with the strongest antibacterial activity were tested against all the bacterial isolates recovered from the milk samples (Study 2). 1,3-thiazoles showed the strongest antibacterial activity, specially compounds 30 and 38, which also showed bactericidal properties according to their minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values. Corynebacterium spp. and Enterobacteriaceae isolates were the most susceptible to compounds 30 and 38. Compounds 30 and 38 are promising targets for new antimicrobial agents.

INDEX TERMS:
Heterocyclic compounds; clinical mastitis; thiazole derivatives; thiazolidinone derivatives; biological activity; antibacterial activity; MIC; MBC

RESUMO:

A mastite causa significativas perdas econômicas à indústria leiteira bovina. O presente estudo teve como objetivo avaliar as propriedades antibacterianas de 39 derivados heterocíclicos (1,3-tiazóis e 4-tiazolidinonas) contra isolados clínicos de mastite em vacas leiteiras. Amostras de leite foram coletadas de vacas com mastite clínica e as espécies bacterianas isoladas foram identificadas por PCR. A atividade antibacteriana foi avaliada pelo método de microdiluição em caldo. Primeiramente, os 39 compostos heterocíclicos foram testados contra quatro isolados bacterianos (Staphylococcus aureus, Streptococcus agalactiae, Corynebacterium bovis e Escherichia coli) escolhidos aleatoriamente dentre os recuperados das amostras de leite (Estudo 1). Posteriormente, compostos com atividade antibacteriana mais forte foram testados contra todos os isolados bacterianos recuperados das amostras de leite (Estudo 2). Os compostos 1,3-tiazóis apresentaram a maior atividade antibacteriana, principalmente os compostos 30 e 38, que também apresentaram propriedades bactericidas de acordo com seus valores de concentração inibitória mínima (CIM) e concentração bactericida mínima (CBM). Os isolados Corynebacterium spp. e Enterobacteriaceae foram os mais suscetíveis aos compostos 30 e 38. Os compostos 30 e 38 mostraram-se promissores como novos agentes antimicrobianos.

TERMOS DE INDEXAÇÃO:
Compostos heterocíclicos; mastite clínica; derivados de tiazóis; derivados de tiazolidinonas; atividade biológica; atividade antibacteriana; CIM; CBM

Introduction

Mastitis causes substantial economic losses to the dairy cattle industry worldwide (De Vliegher et al. 2012De Vliegher S., Fox L.K., Piepers S., McDougall S. & Barkema H.W. 2012. Invited review: mastitis in dairy heifers: nature of the disease, potential impact, prevention, and control. J. Dairy Sci. 95(3):1025-1040. <https://dx.doi.org/10.3168/jds.2010-4074> <PMid:22365187>
https://doi.org/10.3168/jds.2010-4074... ), due to reduced milk production, increased milk disposal and costs for therapy and replacement of animals (Seegers et al. 2003Seegers H., Fourichon C. & Beaudeau F. 2003. Production effects related to mastitis and mastitis economics in dairy cattle herds. Vet. Res. 34(5):475-491. <https://dx.doi.org/10.1051/vetres:2003027> <PMid:14556691>
https://doi.org/10.1051/vetres:2003027... , Halasa et al. 2007Halasa T., Huijps K., Østerås O. & Hogeveen H. 2007. Economic effects of bovine mastitis and mastitis management: a review. Vet. Q. 29(1):18-31. <https://dx.doi.org/10.1080/01652176.2007.9695224> <PMid:17471788>
https://doi.org/10.1080/01652176.2007.96... ). The aetiology of bovine mastitis involves several microbial agents and, in Brazil, Staphylococcus spp., Corynebacterium spp. and Streptococcus spp. are the most common mastitis causative pathogens (Acosta et al. 2016Acosta A.C., Silva L.B.G.d., Medeiros E.S., Pinheiro-Júnior J.W. & Mota R.A. 2016. Mastites em ruminantes no Brasil. Pesq. Vet. Bras. 36(7):565-573. <https://dx.doi.org/10.1590/S0100-736X2016000700001>
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Antimicrobial therapy is an important tool for treating mastitis, but the overuse and misuse of antibiotics may lead to the selection of resistant strains, in particular when therapy is initiated before bacterial susceptibility testing (Thomas et al. 2015Thomas V., Jong A., Moyaert H., Simjee S., El Garch F., Morrissey I., Marion H. & Vallé M. 2015. Antimicrobial susceptibility monitoring of mastitis pathogens isolated from acute cases of clinical mastitis in dairy cows across Europe: VetPath results. Int. J. Antimicrob. Agents 46(1):13-20. <https://dx.doi.org/10.1016/j.ijantimicag.2015.03.013> <PMid:26003836>
https://doi.org/10.1016/j.ijantimicag.20... ). Due to the increasing occurrence of antibiotic resistance, the development of new antimicrobial agents with novel mechanisms of action has become a hot topic (Qiu et al. 2001Qiu X., Janson C.A., Smith W.W., Head M., Lonsdale J. & Konstantinidis A.K. 2001. Refined structures of β-ketoacyl-acyl carrier protein synthase III. J. Mol. Biol. 307(1):341-356. <https://dx.doi.org/10.1006/jmbi.2000.4457>
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The 1,3-thiazoles and 4-thiazolidinones nucleus are found in natural products and have been used to develop synthetic drugs and drug-like molecules with a variety of pharmacological properties. The biological activities of thiazole derivatives include: antibacterial (Abu-Melha et al. 2019Abu-Melha S., Edrees M.M., Salem H.H., Kheder N.A., Gomha S.M. & Abdelaziz M.R. 2019. Synthesis and biological evaluation of some novel thiazole-based heterocycles as potential anticancer and antimicrobial agents. Molecules 24(3):539. <https://dx.doi.org/10.3390/molecules24030539> <PMid:30717217>
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https://doi.org/10.1021/acs.jafc.8b06935... ), antitubercular (Gundlewad & Patil 2018Gundlewad G.B. & Patil B.R. 2018. Synthesis and evaluation of some novel 2-amino-4-aryl thiazoles for antitubercular activity. J. Heterocycl. Chem. 55(3):769-774. <https://dx.doi.org/10.1002/jhet.3098>
https://doi.org/10.1002/jhet.3098... ), antiviral (Güzeldemirci et al. 2018Güzeldemirci N.U., Pehlivan E. & Naesens L. 2018. Synthesis and antiviral activity evaluation of new 4-thiazolidinones bearing an imidazo [2, 1-b] thiazole moiety. Marmara Pharm. J. 22(2)237-248. <https://dx.doi.org/10.12991/MPJ.2018.61>
https://doi.org/10.12991/MPJ.2018.61... ), antitumor (Shaik et al. 2017Shaik S.P., Nayak V.L., Sultana F., Rao A.V.S., Shaik A.B., Babu K.S. & Kamal A. 2017. Design and synthesis of imidazo[2,1-b]thiazole linked triazole conjugates: microtubule-destabilizing agents. Eur. J. Med. Chem. 126:36-51. <https://dx.doi.org/10.1016/j.ejmech.2016.09.060>
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https://doi.org/10.2174/1570163814666170... ), anti-inflammatory (Sinha et al. 2018Sinha S., Doble M. & Manju S. 2018. Design, synthesis and identification of novel substituted 2-amino thiazole analogues as potential anti-inflammatory agents targeting 5-lipoxygenase. Eur. J. Med. Chem. 158:34-50. <https://dx.doi.org/10.1016/j.ejmech.2018.08.098> <PMid:30199704>
https://doi.org/10.1016/j.ejmech.2018.08... ), antioxidant (Afifi et al. 2019Afifi O.S., Shaaban O.G., Abd El Razik H.A., Shams El-Dine S.E.-D.A., Ashour F.A., El-Tombary A.A. & Abu-Serie M.M. 2019. Synthesis and biological evaluation of purine-pyrazole hybrids incorporating thiazole, thiazolidinone or rhodanine moiety as 15-LOX inhibitors endowed with anticancer and antioxidant potential. Bioorg. Chem. 87:821-837. <https://dx.doi.org/10.1016/j.bioorg.2019.03.076> <PMid:30999135>
https://doi.org/10.1016/j.bioorg.2019.03... ), and antiparasitic (Aliança et al. 2017Aliança A.S.d.S., Oliveira A.R., Feitosa A.P.S., Ribeiro K.R.C., Castro M.C.A.B., Leite A.C.L., Alves L.C. & Brayner F.A. 2017. In vitro evaluation of cytotoxicity and leishmanicidal activity of phthalimido-thiazole derivatives. Eur. J. Pharm. Sci. 105:1-10. <https://dx.doi.org/10.1016/j.ejps.2017.05.005> <PMid:28478133>
https://doi.org/10.1016/j.ejps.2017.05.0... ). Similarly, 4-thiazolidinones chemical properties and biological activities include anticancer (Gududuru et al. 2005Gududuru V., Hurh E., Dalton J.T. & Miller D.D. 2005. Discovery of 2-arylthiazolidine-4-carboxylic acid amides as a new class of cytotoxic agents for prostate cancer. J. Med. Chem. 48(7):2584-2588. <https://dx.doi.org/10.1021/jm049208b> <PMid:15801848>
https://doi.org/10.1021/jm049208b... ), antiviral (Rawal et al. 2005Rawal R.K., Prabhakar Y.S., Katti S.B. & De Clercq E. 2005. 2-(Aryl)-3-furan-2-ylmethyl-thiazolidin-4-ones as selective HIV-RT Inhibitors. Bioorg. Med. Chem. 13(24):6771-6776. <https://dx.doi.org/10.1016/j.bmc.2005.07.063> <PMid:16198576>
https://doi.org/10.1016/j.bmc.2005.07.06... ), anti-inflammatory (Ottanà et al. 2005Ottanà R., Maccari R., Barreca M.L., Bruno G., Rotondo A., Rossi A., Chiricosta G., Di Paola R., Sautebin L., Cuzzocrea S. & Vigorita M.G. 2005. 5-Arylidene-2-imino-4-thiazolidinones: design and synthesis of novel anti-inflammatory agents. Bioorg. Med. Chem. 13(13):4243-4252. <https://dx.doi.org/10.1016/j.bmc.2005.04.058> <PMid:15905093>
https://doi.org/10.1016/j.bmc.2005.04.05... ), analgesic (Ashour et al. 2016Ashour H.M.A., El-Ashmawy I.M. & Bayad A.E. 2016. Synthesis and pharmacological evaluation of new pyrazolyl benzenesulfonamides linked to polysubstituted pyrazoles and thiazolidinones as anti-inflammatory and analgesic agents. Monatsh Chem. 147:605-618. <https://dx.doi.org/10.1007/s00706-015-1549-x>
https://doi.org/10.1007/s00706-015-1549-... ), antimicrobial (Liesen et al. 2010Liesen A.P., Aquino T.M., Carvalho C.S., Lima V.T., Araújo J.M., Lima J.G., Faria A.R., Melo E.J.T., Alves A.J., Alves E.W., Alves A.Q. & Góes A.J.S. 2010. Synthesis and evaluation of anti-Toxoplasma gondii and antimicrobial activities of thiosemicarbazides, 4-thiazolidinones and 1,3,4-thiadiazoles. Eur. J. Med. Chem. 45(9):3685-3691. <https://dx.doi.org/10.1016/j.ejmech.2010.05.017> <PMid:20541294>
https://doi.org/10.1016/j.ejmech.2010.05... ), antituberculosis (Babaoglu et al. 2003Babaoglu K., Page M.A., Jones V.C., McNeil M.R., Dong C., Naismith J.H. & Lee R.E. 2003. Novel inhibitors of an emerging target in Mycobacterium tuberculosis; substituted thiazolidinones as inhibitors of dTDP-rhamnose synthesis. Bioorg. Med. Chem. 13(19):3227-3230. <https://dx.doi.org/10.1016/s0960-894x(03)00673-5> <PMid:12951098>
https://doi.org/10.1016/s0960-894x(03)00... ), antiparasitic (Moreira et al. 2012Moreira D.R.M., Costa S.P.M., Hernandes M.Z., Rabello M.M., Oliveira Filho G.B., Melo C.M.L., Rocha L.F., Simone C.A., Ferreira R.S., Fradico J.R.B., Meira C.S., Guimarães E.T., Srivastava R.M., Pereira V.R.A., Soares M.B.P. & Leite A.C.L. 2012. Structural investigation of anti-Trypanosoma cruzi 2-iminothiazolidin-4-ones allows the identification of agents with efficacy in infected mice. J. Med. Chem. 55(24):10918-10936. <https://dx.doi.org/10.1021/jm301518v> <PMid:23167554>
https://doi.org/10.1021/jm301518v... ), among others.

Many researchers have used 1,3-thiazoles and 4-thiazolidinones to improve drug efficacy (Siddiqui et al. 2009Siddiqui N., Arshad M.F., Ahsan W. & Alam M.S. 2009. Thiazoles: a valuable insight into the recent advances and biological activities. Int. J. Pharm. Sci. Drug Res. 1(3):136-143., Ayati et al. 2015Ayati A., Emami S., Asadipour A., Shafiee A. & Foroumadi A. 2015. Recent applications of 1,3-thiazole core structure in the identification of new lead compounds and drug discovery. Eur. J. Med. Chem. 97:699-718. <https://dx.doi.org/10.1016/j.ejmech.2015.04.015> <PMid:25934508>
https://doi.org/10.1016/j.ejmech.2015.04... , Gomes et al. 2016Gomes M.P.A.T., Barbosa M.O., Farias Santiago E., Cardoso M.V.O., Costa N.T.C., Hernandes M.Z., Moreira D.R.M., Silva A.C., Dos Santos T.A.R., Pereira V.R.A., Dos Santosd F.A.B., Pereira G.A.N., Ferreira R.S. & Leite A.C.L. 2016. New 1,3-thiazole derivatives and their biological and ultrastructural effects on Trypanosoma cruzi. Eur. J. Med. Chem. 121:387-398. <https://dx.doi.org/10.1016/j.ejmech.2016.05.050> <PMid:27295485>
https://doi.org/10.1016/j.ejmech.2016.05... ). Therefore, the present study aimed to evaluate the antibacterial properties of 1,3-thiazoles and 4-thiazolidinones derivatives against clinical mastitis isolates from dairy cows.

Materials and Methods

Ethical statement. The present study was approved by the Institutional Animal Care and Use Committee of the “Departamento de Medicina Veterinária” of the “Universidade Federal Rural de Pernambuco” (UFRPE), under the protocol number 079/2014-CEUA. All experimental procedures and the animal care were in strict accordance with the guidelines of the “Conselho Nacional de Controle de Experimentação Animal” (CONCEA; Law 11.794 of October 8, 2008, Decree 6899 of July 15, 2009).

Compounds. The 39 compounds used in the present study, 16 4-thiazolidinones (1-16) (Oliveira Filho et al. 2015Oliveira Filho G.B., Cardoso M.V.O., Espíndola J.W.P., Ferreira L.F.G.R., Simone C.A., Ferreira R.S., Coelho P.L., Meira C.S., Moreira D.R.M., Soares M.B.P. & Lima Leite A.C. 2015. Structural design, synthesis and pharmacological evaluation of 4-thiazolidinones against Trypanosoma cruzi. Bioorg. Med. Chem. 23(23):7478-7486. <https://dx.doi.org/10.1016/j.bmc.2015.10.048> <PMid:26549870>
https://doi.org/10.1016/j.bmc.2015.10.04... ) and 23 1,3-thiazols (17-39) (Cardoso et al. 2014Cardoso M.V., Siqueira L.R.P., Silva E.B., Costa L.B., Hernandes M.Z., Rabello M.M., Ferreira R.S., Cruz L.F., Moreira D.R.M., Pereira V.R.A., Castro M.C.A.B., Bernhardt P.V. & Leite A.C.L. 2014. 2-Pyridyl thiazoles as novel anti-Trypanosoma cruzi agents: structural design, synthesis and pharmacological evaluation. Eur. J. Med. Chem. 86:48-59. <https://dx.doi.org/10.1016/j.ejmech.2014.08.012> <PMid:25147146>
https://doi.org/10.1016/j.ejmech.2014.08... ), were obtained from the “Laboratório de Planejamento em Química Medicinal” of the “Universidade Federal de Pernambuco” (UFPE). The compounds’ structures are presented in Figure 1.

Fig.1.
Structures of the 4-thiazolidinones (1-16) (Oliveira Filho et al. 2015Oliveira Filho G.B., Cardoso M.V.O., Espíndola J.W.P., Ferreira L.F.G.R., Simone C.A., Ferreira R.S., Coelho P.L., Meira C.S., Moreira D.R.M., Soares M.B.P. & Lima Leite A.C. 2015. Structural design, synthesis and pharmacological evaluation of 4-thiazolidinones against Trypanosoma cruzi. Bioorg. Med. Chem. 23(23):7478-7486. <https://dx.doi.org/10.1016/j.bmc.2015.10.048> <PMid:26549870>
https://doi.org/10.1016/j.bmc.2015.10.04... ) and 1,3-thiazols (17-39) (Cardoso et al. 2014Cardoso M.V., Siqueira L.R.P., Silva E.B., Costa L.B., Hernandes M.Z., Rabello M.M., Ferreira R.S., Cruz L.F., Moreira D.R.M., Pereira V.R.A., Castro M.C.A.B., Bernhardt P.V. & Leite A.C.L. 2014. 2-Pyridyl thiazoles as novel anti-Trypanosoma cruzi agents: structural design, synthesis and pharmacological evaluation. Eur. J. Med. Chem. 86:48-59. <https://dx.doi.org/10.1016/j.ejmech.2014.08.012> <PMid:25147146>
https://doi.org/10.1016/j.ejmech.2014.08... ).

Sample selection criteria. Milk samples were collected from 1000 cows from 24 bovine herds from the state of Pernambuco, Brazil as described by (Acosta et al. 2018Acosta A.C., Oliveira P.R.F., Albuquerque L., Silva I.F., Medeiros E.S., Costa M.M., Pinheiro Junior J.W. & Mota R.A. 2018. Frequency of Staphylococcus aureus virulence genes in milk of cows and goats with mastitis. Pesq. Vet. Bras. 38(11):2029-2036. <https://dx.doi.org/10.1590/1678-5150-PVB-5786>
https://doi.org/10.1590/1678-5150-PVB-57... ). Only milk samples from cows with clinical signs of mastitis and that had not been treated with antibiotics for at least three weeks were used in the present study. The criteria for sample inclusion were milk flake, clots, pus or watery secretions and infected quarter showing clinical signs (swelling, heat or pain on palpation).

Milk samples were collected from individual quarters after disinfection of the ostium with 70% ethanol following the recommendations of the National Mastitis Council (1999)National Mastitis Council 1999. Laboratory and field handbook on bovine mastitis. National Mastitis Council, Madison., and transported to the laboratory under refrigeration (4-10°C).

Bacteriological culture. Primary cultures of milk samples were performed by plating 10μL of milk in 5% sheep blood agar and incubated aerobically at 37°C for 24 h to 72 h, considering growth bacterial time. Milk samples with three or more dissimilar colony types were considered contaminated (Hiitiö et al. 2015Hiitiö H., Riva R., Autio T., Pohjanvirta T., Holopainen J., Pyörälä S. & Pelkonen S. 2015. Performance of a real-time PCR assay in routine bovine mastitis diagnostics compared with in-depth conventional culture. J. Dairy Res. 82(2):200-208. <https://dx.doi.org/10.1017/S0022029915000084> <PMid:25704849>
https://doi.org/10.1017/S002202991500008... ). Identification was based on standard phenotypic bacterial identification schemes that included colony and microscopic morphology, Gram stain, growth characteristics, catalase and coagulase activity (Hogan et al. 1999Hogan J., Gonzalez R., Harmon R., Nickerson S., Oliver S., Pankey J. & Smith K.L. 1999. Laboratory Handbook on Bovine Mastitis. National Mastitis Council, Madison, WI, p.6-10.), and thermostable nuclease (TNase) (Rall et al. 2014Rall V.L.M., Miranda E.S., Castilho I.G., Camargo C.H., Langoni H., Guimarães F.F., Araújo Júnior J.P. & Fernandes Júnior A. 2014. Diversity of Staphylococcus species and prevalence of enterotoxin genes isolated from milk of healthy cows and cows with subclinical mastitis. J. Dairy Sci. 97(2):829-837. <https://dx.doi.org/10.3168/jds.2013-7226> <PMid:24359821>
https://doi.org/10.3168/jds.2013-7226... ). Gram negative bacteria were plated onto MacConkey agar (Merck) to screen for members of Enterobacterales order (Saidani et al. 2018Saidani M., Messadi L., Soudani A., Daaloul-Jedidi M., Châtre P., Chehida F.B., Mamlouk A., Mahjoub W., Madec J.-Y. & Haenni M. 2018. Epidemiology, antimicrobial resistance, and extended-spectrum beta-lactamase-producing Enterobacteriaceae in clinical bovine mastitis in Tunisia. Microb. Drug. Resist. 24(8):1242-1248. <https://dx.doi.org/10.1089/mdr.2018.0049> <PMid:29757079>
https://doi.org/10.1089/mdr.2018.0049... ). All bacterial isolates were stored at -20°C in brain/heart infusion broth (Merck) supplemented with 50% glycerol.

DNA extraction and PCR assay. Bacterial species were identified by PCR. Colonies were freshly sub-cultured in brain/heart infusion broth (Merck) and incubated overnight at 37°C for 24 h. Subsequently, DNA was extracted using a commercial kit (Promega) following the manufacturer’s instructions and stored at -20°C. All PCRs were performed in 0.2mL tubes with a final volume of 25μL using the protocol developed by Acosta et al. (2018)Acosta A.C., Oliveira P.R.F., Albuquerque L., Silva I.F., Medeiros E.S., Costa M.M., Pinheiro Junior J.W. & Mota R.A. 2018. Frequency of Staphylococcus aureus virulence genes in milk of cows and goats with mastitis. Pesq. Vet. Bras. 38(11):2029-2036. <https://dx.doi.org/10.1590/1678-5150-PVB-5786>
https://doi.org/10.1590/1678-5150-PVB-57... . PCR primers and annealing temperature can be found in the Table 1. Simplex PCR method for species identification was principally used, and multiplex PCR assay for simultaneous detection of staphylococcal and streptococcal was performed using the protocol developed by Shome et al. (2011)Shome B.R., Das Mitra S., Bhuvana M., Krithiga N., Velu D., Shome R., Isloor S., Barbuddhe S.B. & Rahman H. 2011. Multiplex PCR assay for species identification of bovine mastitis pathogens. J. Appl. Microbiol. 111(6):1349-1356. <https://dx.doi.org/10.1111/j.1365-2672.2011.05169.x> <PMid:21972842>
https://doi.org/10.1111/j.1365-2672.2011... .

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Table 1.
Sequences and characteristics of the oligonucleotide primers

Antimicrobial susceptibility testing. Antibacterial activity was assessed using the broth microdilution method in 96-well microtiter plates (k12-096, KASVI, CH) as per Abu-Melha et al. (2019)Abu-Melha S., Edrees M.M., Salem H.H., Kheder N.A., Gomha S.M. & Abdelaziz M.R. 2019. Synthesis and biological evaluation of some novel thiazole-based heterocycles as potential anticancer and antimicrobial agents. Molecules 24(3):539. <https://dx.doi.org/10.3390/molecules24030539> <PMid:30717217>
https://doi.org/10.3390/molecules2403053... and following the guidelines of the Clinical and Laboratory Standards Institute (CLSI 2018CLSI 2018. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. CLSI document M07-A11, 11th ed., Vol. 38, Clinical and Laboratory Standards Institute, USA, p.112.) for the standard antibacterial drug tetracycline. Because broth microdilution method is costly, time-consuming and labor-intensive, the antimicrobials test was subdivided in two studies. First, were evaluated the antibacterial properties of all 39 heterocyclic compounds and tetracycline against four bacterial isolates randomly chosen from those recovered from the milk samples: Staphylococcus aureus, Streptococcus agalactiae, Corynebacterium bovis and Escherichia coli (Study 1). Then, the heterocyclic compounds with the strongest antibacterial activity were evaluated against all isolates recovered from the milk samples (Study 2).

Sub-cultures were performed in 5% ovine blood agar plates incubated aerobically at 37°C for 24 h. Suspensions were prepared in 0.9% NaCl (w/v) and were adjusted to achieve turbidity equivalent to a 0.5 McFarland standard (approximately 1 to 2 × 108 colony-forming units (CFU)/mL). The final inoculum size in Mueller-Hinton broth (Merck, Germany) dilution was approximately 5 × 105 CFU/mL.

Stock solutions of all compounds tested were prepared in dimethyl sulfoxide (DMSO) at 12.8mg/mL (final concentration). Antimicrobial susceptibility was determined using concentrations derived from serial 2-fold dilutions indexed to the base 2. The final dilutions ranged from 0.625 to 320μɡ/mL for all 39 compounds. Control groups included: culture media only, culture media + microorganism, and culture media + microorganism + DMSO (Fig.2). Tetracycline in sterile distilled water (0.25 to 128μɡ/mL) was used as reference.

Fig.2.
Minimal bactericidal concentration (MBC) of thiazoles compounds. NC (negative control), C+ (positive growth control), C+DMSO (microorganism and solvent - DMSO). Staphylococcus aureus (A and B), Streptococcus agalactiae (C and D), Corynebacterium bovis (E and F) and Escherichia coli (G and H).

Data analysis. Minimal inhibitory concentration (MIC) is the lowest concentration able to inhibit any microbial growth (turbidity). Minimal bactericidal concentration (MBC) is the lowest concentration of an antibiotic required to kill a microorganism. MBC is determined by plating-out samples (Mueller-Hinton agar, Merck, Germany) of completely inhibited dilution cultures and assessing growth (static) or no-growth (cidal) after incubation (Cos et al. 2006Cos P., Vlietinck A.J., Berghe D.V. & Maes L. 2006. Anti-infective potential of natural products: how to develop a stronger in vitro ‘proof-of-concept’. J. Heterocycl. Chem. 106(3):290-302. <https://dx.doi.org/10.1016/j.jep.2006.04.003> <PMid:16698208>
https://doi.org/10.1016/j.jep.2006.04.00... ). The MIC50, MIC90 (MICs at which at least 50% and 90% of the isolates in a test population are inhibited, respectively) (Thomas et al. 2015Thomas V., Jong A., Moyaert H., Simjee S., El Garch F., Morrissey I., Marion H. & Vallé M. 2015. Antimicrobial susceptibility monitoring of mastitis pathogens isolated from acute cases of clinical mastitis in dairy cows across Europe: VetPath results. Int. J. Antimicrob. Agents 46(1):13-20. <https://dx.doi.org/10.1016/j.ijantimicag.2015.03.013> <PMid:26003836>
https://doi.org/10.1016/j.ijantimicag.20... ) and MBC values were determined for all bacterial strains and compounds used in the study. Optical densities were measured by spectrophotometry at 600nm and a growth curve was constructed after measurements at 0 h and 12 h.

Results

Twenty-seven samples of milk were analyzed from cows with clinical mastitis. Three milk samples (11.11%) were contaminated with three or more environmental bacteria concomitantly and were excluded from the study. Of the 24 remaining samples, 11 (40.74%), 4 (14.81%), 3 (11.11%), 3 (11.11%), 2 (7.4%) and 1 (3.7%) were initially identified as Staphylococcus spp., Streptococcus spp., Corynebacterium spp., Enterobacteriaceae, Bacillus spp. and Micrococcus spp., respectively.

Of the 39 heterocyclic compounds tested against the four randomly chosen isolates, 15 (38.46 %), 10 (25.64%), 7 (17.94%) and 7 (17.94%) showed antibacterial activity against Escherichia coli, Streptococcus agalactiae, Staphylococcus aureus and Corynebacterium bovis, respectively (Table 2 and 3). 1,3-thiazoles (17-39), specially compounds 17, 30, 38 and 39 (Table 3), showed the strongest antibacterial activity. All four isolates were susceptible to tetracycline (Table 2).

Thumbnail
Table 2.
Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of 4-thiazolidinones derivatives compounds
Thumbnail
Table 3.
Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of 1,3-thiazoles derivatives compounds

Due to their strong antimicrobial activity against E. coli, S. agalactiae, S. aureus and C. bovis, was decided to evaluate the MIC and MBC of compounds 30 and 38 against the 24 isolates recovered from the milk samples. Compounds 30 and 38 showed a MIC=MBC value or 2*MIC=MBC value against most isolates (Table 4), and compound 38 displayed the most potent in vitro antibacterial activity against all isolates tested, with a MIC50 value of 80μɡ/mL, a MIC90 value of 160μɡ/mL and a MBC value of 40μɡ/mL (Table 4).

Thumbnail
Table 4.
Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of compounds 30 and 38 against the 24 clinical isolates recovered

Corynebacterium spp. and Enterobacteriaceae isolates were the most susceptible to the antibacterial activity of compounds 30 and 38. Compound 30 showed MBC values of 40 and 80μɡ/mL against Corynebacterium spp. and Enterobacteriaceae, respectively, and MIC value of 40μɡ/mL for both isolates. Compound 38 showed MIC values of 10 and 40μɡ/mL against Corynebacterium spp. and Enterobacteriaceae, respectively, and MBC value of 40μɡ/mL against these two isolates (Table 4).

Discussion

Due to their many biological activities, including antibacterial, 1,3-thiazoles and 4-thiazolidinones have attracted considerable attention over the years (Qin et al. 2014Qin Y.-J., Wang P.-F., Makawana J.A., Wang Z.-C., Wang Z.-N., Yan G., Jiang A.-Q. & Zhu H.-L. 2014. Design, synthesis and biological evaluation of metronidazole-thiazole derivatives as antibacterial inhibitors. Bioorg. Med. Chem. 24(22):5279-5283. <https://dx.doi.org/10.1016/j.bmcl.2014.09.054> <PMid:25318998>
https://doi.org/10.1016/j.bmcl.2014.09.0... , Reddy et al. 2016Reddy G.M., Garcia J.R., Reddy V.H., Andrade A.M., Camilo Jr A., Ribeiro R.A.P. & Lazaro S.R. 2016. Synthesis, antimicrobial activity and advances in structure-activity relationships (SARs) of novel tri-substituted thiazole derivatives. Eur. J. Med. Chem. 123:508-513. <https://dx.doi.org/10.1016/j.ejmech.2016.07.062> <PMid:27494167>
https://doi.org/10.1016/j.ejmech.2016.07... , Abu-Melha et al. 2019Abu-Melha S., Edrees M.M., Salem H.H., Kheder N.A., Gomha S.M. & Abdelaziz M.R. 2019. Synthesis and biological evaluation of some novel thiazole-based heterocycles as potential anticancer and antimicrobial agents. Molecules 24(3):539. <https://dx.doi.org/10.3390/molecules24030539> <PMid:30717217>
https://doi.org/10.3390/molecules2403053... , Tratrat et al. 2019Tratrat C., Haroun M., Xenikakis I., Liaras K., Tsolaki E., Eleftheriou P., Petrou A., Aldhubiab B., Attimarad M., Venugopala K., Harsha S., Elsewedy H.S., Geronikaki A. & Soković M. 2019. Design, synthesis, evaluation of antimicrobial activity and docking studies of thiazole-based chalcones. Curr. Top. Med. Chem. 19(5):356-375. <https://dx.doi.org/10.2174/1568026619666190129121933> <PMid:30706816>
https://doi.org/10.2174/1568026619666190... ). In the present study, two 1,3-thiazoles derivatives, compounds 30 and 38, showed significant antimicrobial activity (Table 4) with MIC50 values of 160μɡ/mL and 80μɡ/mL, respectively, which are similar to those previously observed for metronidazole-thiazole derivatives by Qin et al. (2014)Qin Y.-J., Wang P.-F., Makawana J.A., Wang Z.-C., Wang Z.-N., Yan G., Jiang A.-Q. & Zhu H.-L. 2014. Design, synthesis and biological evaluation of metronidazole-thiazole derivatives as antibacterial inhibitors. Bioorg. Med. Chem. 24(22):5279-5283. <https://dx.doi.org/10.1016/j.bmcl.2014.09.054> <PMid:25318998>
https://doi.org/10.1016/j.bmcl.2014.09.0... .

Bacteriostatic agents inhibit the growth of bacterial cells but do not kill them, whereas bactericidal agents kill (French 2006French G. 2006. Bactericidal agents in the treatment of MRSA infections - the potential role of daptomycin. J. Antimicrob. Chemother. 58(6):1107-1117. <https://dx.doi.org/10.1093/jac/dkl393> <PMid:17040922>
https://doi.org/10.1093/jac/dkl393... ). Agents that inhibit ribosome function and protein synthesis tend to be bacteriostatic, whereas those that disrupt the cell wall or membrane, or interfere with essential bacterial enzymes, are likely to be bactericidal (French 2006French G. 2006. Bactericidal agents in the treatment of MRSA infections - the potential role of daptomycin. J. Antimicrob. Chemother. 58(6):1107-1117. <https://dx.doi.org/10.1093/jac/dkl393> <PMid:17040922>
https://doi.org/10.1093/jac/dkl393... ). Bactericidal agents are more advantageous because of the rapid elimination of bacteria and decreased possibility of resistance development or infection recurrence (Finberg et al. 2004Finberg R.W., Moellering R.C., Tally F.P., Craig W.A., Pankey G.A., Dellinger E.P., West M.A., Joshi M., Linden P.K., Rolston K.V., Rotschafer J.C. & Rybak M.J. 2004. The importance of bactericidal drugs: future directions in infectious disease. Clin. Infect. Dis. 39(9):1314-1320. <https://dx.doi.org/10.1086/425009> <PMid:15494908>
https://doi.org/10.1086/425009... ).

In the present study, compounds 30 and 38 showed MIC90 values of 360μɡ/mL and 160μɡ/mL, respectively, and MBC values of 40μɡ/mL and 360μɡ/mL (Table 4), respectively, what demonstrates their bactericidal properties. Similarly, Reddy et al. (2016)Reddy G.M., Garcia J.R., Reddy V.H., Andrade A.M., Camilo Jr A., Ribeiro R.A.P. & Lazaro S.R. 2016. Synthesis, antimicrobial activity and advances in structure-activity relationships (SARs) of novel tri-substituted thiazole derivatives. Eur. J. Med. Chem. 123:508-513. <https://dx.doi.org/10.1016/j.ejmech.2016.07.062> <PMid:27494167>
https://doi.org/10.1016/j.ejmech.2016.07... has shown the bactericidal properties of thiazole derivatives against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Proteus vulgaris with MIC values ranging from 6.25 to 100μɡ/mL and MBC values ranging from 50 to 200μɡ/mL.

Since the literature is not conclusive regarding the bacteria species or clones responsible for the clinical or subclinical cases of bovine mastitis (Ronco et al. 2018Ronco T., Klaas I.C., Stegger M., Svennesen L., Astrup L.B., Farre M. & Pedersen K. 2018. Genomic investigation of Staphylococcus aureus isolates from bulk tank milk and dairy cows with clinical mastitis. Vet. Microbiol. 215:35-42. <https://dx.doi.org/10.1016/j.vetmic.2018.01.003> <PMid:29426404>
https://doi.org/10.1016/j.vetmic.2018.01... , Cheng et al. 2019Cheng J., Qu W., Barkema H.W., Nobrega D.B., Gao J., Liu G., Buck J., Kastelic J.P., Sun H. & Han B. 2019. Antimicrobial resistance profiles of 5 common bovine mastitis pathogens in large Chinese dairy herds. J. Dairy Sci. 102(3):2416-2426. <https://dx.doi.org/10.3168/jds.2018-15135> <PMid:30639013>
https://doi.org/10.3168/jds.2018-15135... , Nüesch-Inderbinen et al. 2019Nüesch-Inderbinen M., Käppeli N., Morach M., Eicher C., Corti S. & Stephan R. 2019. Molecular types, virulence profiles and antimicrobial resistance of Escherichia coli causing bovine mastitis. Vet. Rec. Open. 6(1):e000369. <https://dx.doi.org/10.1136/vetreco-2019-000369> <PMid:31897302>
https://doi.org/10.1136/vetreco-2019-000... ), in the present study was evaluated the antimicrobial properties of the heterocyclic compound against isolates recovered from cows with clinical mastitis as an attempt to be more representative of a real life situation.

The identification of species level is an important task for veterinary diagnostic laboratories. In this study, the most frequently identified species in cows with clinical mastitis were S. aureus (n=3), Staphylococcus simulans (n=3), Staphylococcus hyicus (n=2), Streptococcus agalactiae (n=2) and Corynebacterium bovis (n=2) (Table 4). It is difficult to discriminate between species based on phenotypic differences because there is a lack of unique biochemical markers for species identification in special for coagulase-positive staphylococci (Sasaki et al. 2007Sasaki T., Kikuchi K., Tanaka Y., Takahashi N., Kamata S. & Hiramatsu K. 2007. Reclassification of phenotypically identified Staphylococcus intermedius strains. J. Clin. Microbiol. 45(9):2770-2778. <https://dx.doi.org/10.1128/JCM.00360-07> <PMid:17596353>
https://doi.org/10.1128/JCM.00360-07... ). Molecular diagnostics by PCR have the ability to identify the organism with great sensitivity and specificity and can also distinguish between very closely related organisms. These molecular diagnostic methods have many advantages over the traditional bacteriology techniques in terms of low cost and accurate detection (Ashraf et al. 2017Ashraf A., Imran M., Yaqub T., Tayyab M., Shehzad W. & Thomson P.C. 2017. A novel multiplex PCR assay for simultaneous detection of nine clinically significant bacterial pathogens associated with bovine mastitis. Mol. Cell. Probes 33:57-64. <https://dx.doi.org/10.1016/j.mcp.2017.03.004> <PMid:28336361>
https://doi.org/10.1016/j.mcp.2017.03.00... ).

Because of the importance of antimicrobial therapies and antibiotic resistance for human and animal health (Ball 1999Ball P. 1999. Therapy for pneumococcal infection at the millennium: doubts and certainties. Am. J. Med. 107(1A):77S-85S. <https://dx.doi.org/10.1016/s0002-9343(99)00104-7> <PMid:10451013>
https://doi.org/10.1016/s0002-9343(99)00... , Ball et al. 2002Ball P., Baquero F., Cars O., File T., Garau J., Klugman K., Low D., Rubinstein E. & Wise R. 2002. Antibiotic therapy of community respiratory tract infections: strategies for optimal outcomes and minimized resistance emergence. J. Antimicrob. Chemother. 49(1):31-40. <https://dx.doi.org/10.1093/jac/49.1.31> <PMid:11751764>
https://doi.org/10.1093/jac/49.1.31... ), the development of new antimicrobial agents (Qiu et al. 2001Qiu X., Janson C.A., Smith W.W., Head M., Lonsdale J. & Konstantinidis A.K. 2001. Refined structures of β-ketoacyl-acyl carrier protein synthase III. J. Mol. Biol. 307(1):341-356. <https://dx.doi.org/10.1006/jmbi.2000.4457>
https://doi.org/10.1006/jmbi.2000.4457... , Rafi et al. 2006Rafi S.B., Cui G., Song K., Cheng X., Tonge P.J. & Simmerling C. 2006. Insight through molecular mechanics Poisson-Boltzmann surface area calculations into the binding affinity of triclosan and three analogues for FabI, the E. coli enoyl reductase. J. Med. Chem. 49(15):4574-4580. <https://dx.doi.org/10.1021/jm060222t> <PMid:16854062>
https://doi.org/10.1021/jm060222t... , Qin et al. 2014Qin Y.-J., Wang P.-F., Makawana J.A., Wang Z.-C., Wang Z.-N., Yan G., Jiang A.-Q. & Zhu H.-L. 2014. Design, synthesis and biological evaluation of metronidazole-thiazole derivatives as antibacterial inhibitors. Bioorg. Med. Chem. 24(22):5279-5283. <https://dx.doi.org/10.1016/j.bmcl.2014.09.054> <PMid:25318998>
https://doi.org/10.1016/j.bmcl.2014.09.0... ) and studies that monitor the pathogens and their antibiotic resistance status (Saidani et al. 2018Saidani M., Messadi L., Soudani A., Daaloul-Jedidi M., Châtre P., Chehida F.B., Mamlouk A., Mahjoub W., Madec J.-Y. & Haenni M. 2018. Epidemiology, antimicrobial resistance, and extended-spectrum beta-lactamase-producing Enterobacteriaceae in clinical bovine mastitis in Tunisia. Microb. Drug. Resist. 24(8):1242-1248. <https://dx.doi.org/10.1089/mdr.2018.0049> <PMid:29757079>
https://doi.org/10.1089/mdr.2018.0049... , Schabauer et al. 2018Schabauer A., Pinior B., Gruber C.-M., Firth C.L., Käsbohrer A., Wagner M., Rychli K. & Obritzhauser W. 2018. The relationship between clinical signs and microbiological species, spa type, and antimicrobial resistance in bovine mastitis cases in Austria. Vet. Microbiol. 227:52-60. <https://dx.doi.org/10.1016/j.vetmic.2018.10.024> <PMid:30473352>
https://doi.org/10.1016/j.vetmic.2018.10... ) are of extreme importance. Although the MIC and MBC results found in the present study do not reflect the actual antimicrobial susceptibility of the pathogens studied, the results should serve as a reference baseline for future studies and development of new antimicrobial agents.

Conclusion

The antibacterial compounds presenting a 1,3-thiazoles nucleus showed the strongest antibacterial activity. Two compounds, 30 and 38, showed bactericidal effects against several of the bacterial isolates evaluated (Staphylococcus aureus [n=3], Staphylococcus simulans [n=3], Staphylococcus hyicus [n=2], Staphylococcus xylosus [n=1], Streptococcus agalactiae [n=2], Streptococcus uberis [n=1], Streptococcus spp. [n=1], Corynebacterium bovis [n=2], Corynebacterium spp. [n=1], Escherichia coli [n=1], Enterobacteriaceae [n=2], Bacillus spp. [n=2] and Micrococcus spp. [n=1]), being promising targets for the development of new broad-spectrum antimicrobial agents.

Acknowledgements

This study was financially supported by the “Conselho Nacional de Desenvolvimento Científico e Tecnológico” (CNPq - grant number: 150784/2017-1 and 409107/2018-2). The Medical Chemistry Planning Laboratory is thankful to financial support from CNPq (grant number 427078/2016-4) and “Fundação de Amparo à Ciência e Tecnologia de Pernambuco” (FACEPE - grant number APQ-0289-4.03/13 and APQ-0350-4.03/18).

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Publication Dates

  • Publication in this collection
    22 Oct 2021
  • Date of issue
    2021

History

  • Received
    11 July 2021
  • Accepted
    22 July 2021
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