Hostname: page-component-78c5997874-lj6df Total loading time: 0 Render date: 2024-11-07T23:32:25.942Z Has data issue: false hasContentIssue false
  • English
  • Français

Novel approaches to discovery of antibacterial agents

Published online by Cambridge University Press:  13 November 2008

Patricia L. Taylor  and
Gerard D. Wright
Patricia L. Taylor
Affiliation:
Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main St. W., Hamilton, ON, L8N 3Z5, Canada
Gerard D. Wright*
Affiliation:
Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main St. W., Hamilton, ON, L8N 3Z5, Canada
*
*Corresponding author. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Antimicrobial resistance is a rapidly increasing problem impacting the successful treatment of bacterial infectious disease. To combat resistance, the development of new treatment options is required. Recent advances in technology have aided in the discovery of novel antibacterial agents, specifically through genome mining for novel natural product biosynthetic gene clusters and improved small molecule high-throughput screening methods. Novel targets such as lipopolysaccharide and fatty acid biosyntheses have been identified by essential gene studies, representing a shift from traditional antibiotic targets. Finally, inhibiting non-essential genes with small molecules is being explored as a method for rescuing the activity of ‘old’ antibiotics, providing a novel synergistic approach to antimicrobial discovery.

Keywords

antibiotic resistancenovel targetsgenome mininghigh-throughput screeningsynergychemical genetics
Type
Review Article
Information
Animal Health Research Reviews , Volume 9 , Issue 2: Symposium on Antimicrobial Resistance in Bacteria from Animals , December 2008 , pp. 237 - 246
Copyright
Copyright © Cambridge University Press 2008

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Ackermann, G and Rodloff, AC (2003). Drugs of the 21st century: telithromycin (HMR 3647) – the first ketolide. Journal of Antimicrobial Chemotherapy 51: 497–511.CrossRefGoogle ScholarPubMed
Andries, K, Verhasselt, P, Guillemont, J, Gohlmann, HW, Neefs, JM, Winkler, H, Van Gestel, J, Timmerman, P, Zhu, M, Lee, E, Williams, P, de Chaffoy, D, Huitric, E, Hoffner, S, Cambau, E, Truffot-Pernot, C, Lounis, N and Jarlier, V (2005). A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307: 223–227.CrossRefGoogle ScholarPubMed
Baba, T, Huan, HC, Datsenko, K, Wanner, BL and Mori, H (2008). The applications of systematic in-frame, single-gene knockout mutant collection of Escherichia coli K-12. Methods in Molecular Biology 416: 183–194.CrossRefGoogle ScholarPubMed
Ball, P (2007). Conclusions: the future of antimicrobial therapy – augmentin and beyond. International Journal of Antimicrobial Agents 30 (suppl. 2): S139–S141.CrossRefGoogle ScholarPubMed
Baltz, RH (2005). Antibiotic discovery from actinomycetes: will a renaissance follow the decline and fall? SIM News 55: 186–196.Google Scholar
Baltz, RH (2008). Renaissance in antibacterial discovery from actinomycetes. Current Opinion in Pharmacology 8: 1–7.CrossRefGoogle ScholarPubMed
Baltz, RH, Miao, V and Wrigley, SK (2005). Natural products to drugs: daptomycin and related lipopeptide antibiotics. Natural Product Reports 22: 717–741.CrossRefGoogle ScholarPubMed
Banskota, AH, McAlpine, JB, Sorensen, D, Aouidate, M, Piraee, M, Alarco, AM, Omura, S, Shiomi, K, Farnet, CM and Zazopoulos, E (2006a). Isolation and identification of three new 5-alkenyl-3,3(2H)-furanones from two streptomyces species using a genomic screening approach. Journal of Antibiotics 59: 168–176.CrossRefGoogle ScholarPubMed
Banskota, AH, McAlpine, JB, Sorensen, D, Ibrahim, A, Aouidate, M, Piraee, M, Alarco, AM, Farnet, CM and Zazopoulos, E (2006b). Genomic analyses lead to novel secondary metabolites. Part 3. ECO-0501, a novel antibacterial of a new class. Journal of Antibiotics 59: 533–542.CrossRefGoogle ScholarPubMed
Barb, AW, McClerren, AL, Snehelatha, K, Reynolds, CM, Zhou, P and Raetz, CR (2007). Inhibition of lipid A biosynthesis as the primary mechanism of CHIR-090 antibiotic activity in Escherichia coli. Biochemistry 46: 3793–3802.CrossRefGoogle ScholarPubMed
Brickner, SJ, Barbachyn, MR, Hutchinson, DK and Manninen, PR (2008). Linezolid (ZYVOX), the first member of a completely new class of antibacterial agents for treatment of serious Gram-positive infections. Journal of Medicinal Chemistry 51: 1981–1990.CrossRefGoogle ScholarPubMed
Brotz-Oesterhelt, H, Beyer, D, Kroll, HP, Endermann, R, Ladel, C, Schroeder, W, Hinzen, B, Raddatz, S, Paulsen, H, Henninger, K, Bandow, JE, Sahl, HG and Labischinski, H (2005). Dysregulation of bacterial proteolytic machinery by a new class of antibiotics. Nature Medicine 11: 1082–1087.CrossRefGoogle ScholarPubMed
Brown, ED and Wright, GD (2005). New targets and screening approaches in antimicrobial drug discovery. Chemical Reviews 105: 759–774.CrossRefGoogle ScholarPubMed
Butland, G, Babu, M, Diaz-Mejia, JJ, Bohdana, F, Phanse, S, Gold, B, Yang, W, Li, J, Gagarinova, AG, Pogoutse, O, Mori, H, Wanner, BL, Lo, H, Wasniewski, J, Christopolous, C, Ali, M, Venn, P, Safavi-Naini, A, Sourour, N, Caron, S, Choi, JY, Laigle, L, Nazarians-Armavil, A, Deshpande, A, Joe, S, Datsenko, KA, Yamamoto, N, Andrews, BJ, Boone, C, Ding, H, Sheikh, B, Moreno-Hagelseib, G, Greenblatt, JF and Emili, A (2008). eSGA: E. coli synthetic genetic array analysis. Nature Methods 5: 789–795.CrossRefGoogle ScholarPubMed
Cegelski, L, Marshall, GR, Eldridge, GR and Hultgren, SJ (2008). The biology and future prospects of antivirulence therapies. Nature Reviews Microbiology 6: 17–27.CrossRefGoogle ScholarPubMed
Challis, GL and Ravel, J (2000). Coelichelin, a new peptide siderophore encoded by the Streptomyces coelicolor genome: structure prediction from the sequence of its non-ribosomal peptide synthetase. FEMS Microbiology Letters 187: 111–114.CrossRefGoogle ScholarPubMed
Dargatz, DA and Traub-Dargatz, JL (2004). Multidrug-resistant Salmonella and nosocomial infections. Veterinary Clinics of North America: Equine Practice 20: 587–600.Google ScholarPubMed
De Leon, GP, Elowe, NH, Koteva, KP, Valvano, MA and Wright, GD (2006). An in vitro screen of bacterial lipopolysaccharide biosynthetic enzymes identifies an inhibitor of ADP-heptose biosynthesis. Chemistry and Biology 13: 437–441.CrossRefGoogle Scholar
Escaich, S (2008). Antivirulence as a new antibacterial approach for chemotherapy. Current Opinion in Chemical Biology 12: 1–9.CrossRefGoogle ScholarPubMed
Fenical, W and Jensen, PR (2006). Developing a new resource for drug discovery: marine actinomycete bacteria. Nature Chemical Biology 2: 666–673.CrossRefGoogle ScholarPubMed
Fiedler, HP, Bruntner, C, Bull, AT, Ward, AC, Goodfellow, M, Potterat, O, Puder, C and Mihm, G (2005). Marine actinomycetes as a source of novel secondary metabolites. Antonie Van Leeuwenhoek 87: 37–42.CrossRefGoogle ScholarPubMed
Forsyth, RA, Haselbeck, RJ, Ohlsen, KL, Yamamoto, RT, Xu, H, Trawick, JD, Wall, D, Wang, L, Brown-Driver, V, Froelich, JM, C, KG, King, P, McCarthy, M, Malone, C, Misiner, B, Robbins, D, Tan, Z, Zhu, Zy ZY, Carr, G, Mosca, DA, Zamudio, C, Foulkes, JG and Zyskind, JW (2002). A genome-wide strategy for the identification of essential genes in Staphylococcus aureus. Molecular Microbiology 43: 1387–1400.CrossRefGoogle ScholarPubMed
Fraise, AP (2006). Tigecycline: the answer to beta-lactam and fluoroquinolone resistance? Journal of Infection 53: 293–300.CrossRefGoogle ScholarPubMed
Fukumoto, A, Kim, YP, Matsumoto, A, Takahashi, Y, Shiomi, K, Tomoda, H and Omura, S (2008). Cyslabdan, a new potentiator of imipenem activity against methicillin-resistant Staphylococcus aureus, produced by Streptomyces sp. K04-0144. I. Taxonomy, fermentation, isolation and structural elucidation. Journal of Antibiotics 61: 1–6.CrossRefGoogle ScholarPubMed
, Fan, S, Bilderbeck, A, Li, M, Pang, H and Tao, S (2008). Comparative analysis of essential genes and nonessential genes in Escherichia coli K12. Molecular Genetics and Genomics: MGG 279: 87–94.Google Scholar
Hancock, RE and Sahl, HG (2006). Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nature Biotechnology 24: 1551–1557.CrossRefGoogle ScholarPubMed
Khalil, H, Chen, T, Riffon, R, Wang, R and Wang, Z (2008). Synergy between polyethylenimine and different families of antibiotics against a resistant clinical isolate of Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy 52: 1635–1641.CrossRefGoogle ScholarPubMed
Kobayashi, K, Ehrlich, SD, Albertini, A, Amati, G, Andersen, KK, Arnaud, M, Asai, K, Ashikaga, S, Aymerich, S, Bessieres, P, Boland, F, Brignell, SC, Bron, S, Bunai, K, Chapuis, J, Christiansen, LC, Danchin, A, Debarbouille, M, Dervyn, E, Deuerling, E, Devine, K, Devine, SK, Dreesen, O, Errington, J, Fillinger, S, Foster, SJ, Fujita, Y, Galizzi, A, Gardan, R, Eschevins, C, Fukushima, T, Haga, K, Harwood, CR, Hecker, M, Hosoya, D, Hullo, MF, Kakeshita, H, Karamata, D, Kasahara, Y, Kawamura, F, Koga, K, Koski, P, Kuwana, R, Imamura, D, Ishimaru, M, Ishikawa, S, Ishio, I, Le Coq, D, Masson, A, Mauel, C, Meima, R, Mellado, RP, Moir, A, Moriya, S, Nagakawa, E, Nanamiya, H, Nakai, S, Nygaard, P, Ogura, M, Ohanan, T, O'Reilly, M, O'Rourke, M, Pragai, Z, Pooley, HM, Rapoport, G, Rawlins, JP, Rivas, LA, Rivolta, C, Sadaie, A, Sadaie, Y, Sarvas, M, Sato, T, Saxild, HH, Scanlan, E, Schumann, W, Seegers, JF, Sekiguchi, J, Sekowska, A, Seror, SJ, Simon, M, Stragier, P, Studer, R, Takamatsu, H, Tanaka, T, Takeuchi, M, Thomaides, HB, Vagner, V, van Dijl, JM, Watabe, K, Wipat, A, Yamamoto, H, Yamamoto, M, Yamamoto, Y, Yamane, K, Yata, K, Yoshida, K, Yoshikawa, H, Zuber, U and Ogasawara, N (2003). Essential Bacillus subtilis genes. Proceedings of the National Academy of Sciences, USA 100: 4678–4683.CrossRefGoogle ScholarPubMed
Lautru, S, Deeth, RJ, Bailey, LM and Challis, GL (2005). Discovery of a new peptide natural product by Streptomyces coelicolor genome mining. Nature Chemical Biology 1: 265–269.CrossRefGoogle ScholarPubMed
Leonard, FC and Markey, BK (2008). Methicillin-resistant Staphylococcus aureus in animals: a review. Veterinary Journal 175: 27–36.CrossRefGoogle ScholarPubMed
Livermore, DM and Woodford, N (2006). The beta-lactamase threat in Enterobacteriaceae, Pseudomonas and Acinetobacter. Trends in Microbiology 14: 413–420.CrossRefGoogle ScholarPubMed
Lock, RL and Harry, EJ (2008). Cell-division inhibitors: new insights for future antibiotics. Nature Reviews Drug Discovery 7: 324–338.CrossRefGoogle ScholarPubMed
Lomovskaya, O and Bostian, KA (2006). Practical applications and feasibility of efflux pump inhibitors in the clinic – a vision for applied use. Biochemical Pharmacology 71: 910–918.CrossRefGoogle Scholar
Loutet, SA, Flannagan, RS, Kooi, C, Sokol, PA and Valvano, MA (2006). A complete lipopolysaccharide inner core oligosaccharide is required for resistance of Burkholderia cenocepacia to antimicrobial peptides and bacterial survival in vivo. Journal of Bacteriology 188: 2073–2080.CrossRefGoogle ScholarPubMed
Lu, H and Tonge, PJ (2008). Inhibitors of FabI, an enzyme drug target in the bacterial fatty acid biosynthesis pathway. Accounts of Chemical Research 41: 11–20.CrossRefGoogle ScholarPubMed
Mahamoud, A, Chevalier, J, Alibert-Franco, S, Kern, WV and Pages, JM (2007). Antibiotic efflux pumps in Gram-negative bacteria: the inhibitor response strategy. Journal of Antimicrobial Chemotherapy 59: 1223–1229.CrossRefGoogle ScholarPubMed
Marquez, B (2005). Bacterial efflux systems and efflux pumps inhibitors. Biochimie 87: 1137–1147.CrossRefGoogle ScholarPubMed
McArthur, F, Andersson, CE, Loutet, S, Mowbray, SL and Valvano, MA (2005). Functional analysis of the glycero-manno-heptose 7-phosphate kinase domain from the bifunctional HldE protein, which is involved in ADP-l-glycero-d-manno-heptose biosynthesis. Journal of Bacteriology 187: 5292–5300.CrossRefGoogle ScholarPubMed
Miethke, M and Marahiel, MA (2007). Siderophore-based iron acquisition and pathogen control. Microbiology Molecular Biology Reviews 71: 413–451.CrossRefGoogle ScholarPubMed
O'Shea, R and Moser, HE (2008). Physicochemical properties of antibacterial compounds: implications for drug discovery. Journal of Medicinal Chemistry 51: 2871–2878.CrossRefGoogle ScholarPubMed
Oteo, J, Campos, J, Lazaro, E, Cuevas, O, Garcia-Cobos, S, Perez-Vazquez, M and de Abajo, FJ (2008). Increased amoxicillin-clavulanic acid resistance in Escherichia coli blood isolates, Spain. Emerging Infectious Diseases 14: 1259–1262.CrossRefGoogle ScholarPubMed
Pages, JM, Masi, M and Barbe, J (2005). Inhibitors of efflux pumps in Gram-negative bacteria. Trends in Molecular Medicine 11: 382–389.CrossRefGoogle ScholarPubMed
Payne, DJ, Gwynn, MN, Holmes, DJ and Pompliano, DL (2007). Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nature Reviews Drug Discovery 6: 29–40.CrossRefGoogle ScholarPubMed
Piddock, LJ (2006). Multidrug-resistance efflux pumps – not just for resistance. Nature Reviews Microbiology 4: 629–636.CrossRefGoogle Scholar
Raetz, CR and Whitfield, C (2002). Lipopolysaccharide endotoxins. Annual Reviews of Biochemistry 71: 635–700.CrossRefGoogle ScholarPubMed
Rasmussen, TB and Givskov, M (2006). Quorum-sensing inhibitors as anti-pathogenic drugs. International Journal of Molecular Medicine 296: 149–161.Google ScholarPubMed
Rice, LB (2006). Challenges in identifying new antimicrobial agents effective for treating infections with Acinetobacter baumannii and Pseudomonas aeruginosa. Clinical Infectious Diseases 43 (suppl. 2): S100–S105.CrossRefGoogle ScholarPubMed
Saha, S, Savage, PB and Bal, M (2008). Enhancement of the efficacy of erythromycin in multiple antibiotic-resistant Gram-negative bacterial pathogens. Journal of Applied Microbiology 105: 822–828.CrossRefGoogle ScholarPubMed
Sitaram, N and Nagaraj, R (2002). The therapeutic potential of host-defense antimicrobial peptides. Current Drug Targets 3: 259–267.CrossRefGoogle ScholarPubMed
Stavri, M, Piddock, LJ and Gibbons, S (2007). Bacterial efflux pump inhibitors from natural sources. Journal of Antimicrobial Chemotherapy 59: 1247–1260.CrossRefGoogle ScholarPubMed
Stokes, NR, Sievers, J, Barker, S, Bennett, JM, Brown, DR, Collins, I, Errington, VM, Foulger, D, Hall, M, Halsey, R, Johnson, H, Rose, V, Thomaides, HB, Haydon, DJ, Czaplewski, LG and Errington, J (2005). Novel inhibitors of bacterial cytokinesis identified by a cell-based antibiotic screening assay. Journal of Biological Chemistry 280: 39709–39715.CrossRefGoogle ScholarPubMed
Talbot, GH, Bradley, J, Edwards, JE Jr, Gilbert, D, Scheld, M and Bartlett, JG (2006). Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. Clinical Infectious Diseases 42: 657–668.CrossRefGoogle ScholarPubMed
Taylor, PL, Blakely, KM, de Leon, GP, Walker, JR, McArthur, F, Evdokimova, E, Zhang, K, Valvano, MA, Wright, GD and Junop, MS (2008). Structure and function of sedoheptulose-7-phosphate isomerase, a critical enzyme for lipopolysaccharide biosynthesis and a target for antibiotic adjuvants. Journal of Biological Chemistry 283: 2835–2845.CrossRefGoogle Scholar
Townsend, ML, Pound, MW and Drew, RH (2006). Tigecycline: a new glycylcycline antimicrobial. International Journal of Clinical Practice 60: 1662–1672.CrossRefGoogle ScholarPubMed
Valvano, MA, Messner, P and Kosma, P (2002). Novel pathways for biosynthesis of nucleotide-activated glycero-manno-heptose precursors of bacterial glycoproteins and cell surface polysaccharides. Microbiology 148: 1979–1989.CrossRefGoogle ScholarPubMed
Walsh, CT (2003) Antibiotics: Actions, Origins, Resistance. Washington, DC: ASM Press.CrossRefGoogle Scholar
Wang, J, Soisson, SM, Young, K, Shoop, W, Kodali, S, Galgoci, A, Painter, R, Parthasarathy, G, Tang, YS, Cummings, R, Ha, S, Dorso, K, Motyl, M, Jayasuriya, H, Ondeyka, J, Herath, K, Zhang, C, Hernandez, L, Allocco, J, Basilio, A, Tormo, JR, Genilloud, O, Vicente, F, Pelaez, F, Colwell, L, Lee, SH, Michael, B, Felcetto, T, Gill, C, Silver, LL, Hermes, JD, Bartizal, K, Barrett, J, Schmatz, D, Becker, JW, Cully, D and Singh, SB (2006). Platensimycin is a selective FabF inhibitor with potent antibiotic properties. Nature 441: 358–361.CrossRefGoogle ScholarPubMed
White, AR, Kaye, C, Poupard, J, Pypstra, R, Woodnutt, G and Wynne, B (2004). Augmentin (amoxicillin/clavulanate) in the treatment of community-acquired respiratory tract infection: a review of the continuing development of an innovative antimicrobial agent. Journal of Antimicrobial Chemotherapy 53 (suppl. 1): 13–20.CrossRefGoogle ScholarPubMed
Wilson, DN, Schluenzen, F, Harms, JM, Starosta, AL, Connell, SR and Fucini, P (2008). The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning. Proceedings of the National Academy of Sciences, USA 105: 13339–13344.CrossRefGoogle ScholarPubMed
Wisell, KT, Kahlmeter, G and Giske, CG (2008). Trimethoprim and enterococci in urinary tract infections: new perspectives on an old issue. Journal of Antimicrobial Chemotherapy 62: 35–40.CrossRefGoogle Scholar
Yethon, JA and Whitfield, C (2001). Lipopolysaccharide as a target for the development of novel therapeutics in Gram-negative bacteria. Current Drug Targets: Infectious Disorders 1: 91–106.Google ScholarPubMed
Young, K, Jayasuriya, H, Ondeyka, JG, Herath, K, Zhang, C, Kodali, S, Galgoci, A, Painter, R, Brown-Driver, V, Yamamoto, R, Silver, LL, Zheng, Y, Ventura, JI, Sigmund, J, Ha, S, Basilio, A, Vicente, F, Tormo, JR, Pelaez, F, Youngman, P, Cully, D, Barrett, JF, Schmatz, D, Singh, SB and Wang, J (2006). Discovery of FabH/FabF inhibitors from natural products. Antimicrobial Agents and Chemotherapy 50: 519–526.CrossRefGoogle ScholarPubMed
Zazopoulos, E, Huang, K, Staffa, A, Liu, W, Bachmann, BO, Nonaka, K, Ahlert, J, Thorson, JS, Shen, B and Farnet, CM (2003). A genomics-guided approach for discovering and expressing cryptic metabolic pathways. Nature Biotechnology 21: 187–190.CrossRefGoogle ScholarPubMed
Zolli-Juran, M, Cechetto, JD, Hartlen, R, Daigle, DM and Brown, ED (2003). High throughput screening identifies novel inhibitors of Escherichia coli dihydrofolate reductase that are competitive with dihydrofolate. Bioorganic and Medicinal Chemistry Letters 13: 2493–2496.CrossRefGoogle ScholarPubMed