Abstract
Bacterial resistance against established antibiotics is becoming an increasingly important global healthcare problem. Despite enormous efforts, the number of therapeutically useful compounds that emerge from chemical derivatisation programs, which aim at circumventing mechanisms of resistance, is continuously decreasing and no truly novel class of compound has been introduced into therapy for nearly four decades. Hopes are now set on a thorough elucidation of bacterial cell functions to identify new bacterial target sites, and on the development of novel compounds with alternative modes of action. The pursuit of these strategies is rendered possible by employment of biotechnologically based methods such as in vivo modification of biosynthetic routes in antibiotic-producing organisms, large-scale screening assays with isolated bacterial targets, the molecular profiling of bacterial genomes and proteomes, and the development and clinical use of biochips as diagnostic tools for rapid identification and characterization of pathogenic strains. As one of the most promising class of compounds known to date with unique modes of action that escape most known mechanisms of resistance, peptic agents have recently came under the focus of anti-infective research, just as extracellular signalling molecules (autoinducer) have emerged as new bacterial target sites.
Similar content being viewed by others
References
Ali RS, Falconer A, Ikram M, Bissett CE, Cerio R, Quinn AG (2001) Expression of the peptide antibiotics human beta defensin 1 and human beta defensin 2 in normal human skin. J Invest Dermatol 117:106–111
Aretz W, Meiwes J, Seibert G, Vobis G, Wink J (2000) Friulimicins: novel lipopetide antibiotics with peptidoglycan synthesis inhibiting activity from Actinoplanes friulensis sp. Nov. I. Taxonomic studies of the producing microorganism and fermentation. J Antibiot 53:807–815
Arroyo M, de la Mata I, Acebal C, Castillon MP (2003) Biotechnological application of penicillin acylases: state of the art. Appl Microbiol Biotechnol 60:507–514
Bandak, SI, Tumak MR, Allen BS, Bolzon LD, Preston DA (2000) Assessment of the susceptibility of Streptococcus pneumoniae to cefaclor and loracarbef in 13 countries. J Chemother 12:299–305
Bauer F, Schweimer K, Kluver E, Conejo-Garcia J, Forssmann W, Rosch P, Adermann K, Sticht H (2001) Structure determination of human and murine beta defensins reveal structural conservation in the absence of significant sequence similarity. Protein Sci 10:2470–2479
Bax R, Mullan N, Verhoef J (2000) The millennium bugs—the need for and development of new antibacterials. Int J Antimicrob Agents 16:51–59
Bechinger B (2001) Solid state NMR investigations of interaction contributions that determine the alignment of helical polypeptides in biological membranes. FEBS Lett 504:161–165
Blondelle SE (2001) Synthetic combinatorial libraries: an emerging approach toward the identification of novel antibiotics. In: Lohner K (ed) Development of novel antimicrobial agents: emerging strategies. Horizon, Wymondham, Norfolk, UK, pp 199–216
Blondelle SE, Lohner K (2000) Combinatorial libraries: a tool to design antimicrobial and antifungal peptides analogues having lytic specificities for structure-activity relationship studies. Biopolymers 55:74–87
Blondelle SE, Takahashi E, Houghten RA, Perez-Paya E (1996) Rapid identification of compounds having enhanced microbial activity using conformationally defined combinatorial libraries. Biochem J 313:141–147
Boeck LD, Wetzel RW (1990) A54145, a new lipopeptide antibiotic complex: factor control through precursor-directed biosynthesis. J Antibiotics 43:607–615
Boeck LD, Papiska HR, Wetzel RW, Mynderse JS, Fukuda DS, Mertz FP, Berry DM (1990) A54145, a new lipopeptide antibiotic complex: discovery, taxonomy, fermentation and HPLC. J Antibiotics 43:587–593
Bonnefoy A, Guitton M, Delachaume C, Le Priol P, Girard AM (2001) In vivo efficacy of the new ketolide telithromycin (HMR 3647) in murine infection models. Antimicrob Agents Chemother 45:1688–1692
Branny P, Pearson JP, Everett CP, Köhler T, Iglewski BH, van Delden C (2001) Inhibition of quorum sensing by a Pseudomonas aeruginosa dksA homologue. J Bacteriol 183:1531–1539
Breukink E, Wiedemann I, Van Kraaij C, Kuipers OP, Sahl HG, De Kruijff (1999) Use of the cell wall precursor lipid II by pore forming peptide antibiotic. Science 286:2361–2364
Bryson HM, Spencer CM (1996) Quinupristin-Dalfopristin. Drugs 52:406–415
Cane DE, Walsh CT (1999) The parallel and convergent universes of polyketide synthases and non-ribosomal peptide synthases. Chem Biol 6:R319–R325
Capobianco JO, Cao Z, Shortridge VD, Ma Z, Flamm RK, Zhong P (2000) Studies of the novel ketolide ABT-773: transport, binding to ribosomes and inhibition of protein synthesis in Streptococcus pneumoniae. Antimicrob Agents Chemother 44:1562–1567
Cassell GH (1997) Emergent antibiotic resistance: health risks and economic impact. FEMS Immunol Med Microbiol 18:271–274
Chadwick DJ, Goode J (1997) Antibiotic resistance: origins, evolution, selection and spread. Wiley, New York
Chalker AF, Lunsford RD (2002) Rational identification of new antibacterial drug targets that are essential for viability using a genomic based approach. Pharmacol Ther 95:1–20
Chopra I, Hodgson J, Metcalf B, Poste G (1997) The search for antimicrobial agents effective against bacteria resistant to multiple antibiotics. Antimicrob Agents Chemother 41:497–503
Coque TM, Tomayko JF, Ricke SC, Okhuysen PC (1996) Vancomycin resistant enterococci from nosocomial, community and animal sources in the United States. Antimicrob Agents Chemother 40:2605–2609
Cormican MG, Jones RN (1996) Emerging resistance to antimicrobial agents in Gram-positive bacteria. Drugs 51 Suppl 1:1–16
Costerton JW, Stewart PS (2001) Battling biofilms. Sci Am 285:74–81
Counter FT, Allen NE, Fukuda DS, Hobbs JN, Ott J, Ensminger PW, Mynderse JS, Preston DA, Wu, CYE (1990) A54145, a new lipopetide antibiotic complex: microbiological evaluation. J Antibiot 43:616–622
Cuzin M (2001) DNA-chips: a new tool for genetic analysis and diagnostics. Transfus Clin Biol 8:291–296
Du L, Shen B (2001) Biosynthesis of hybrid peptide-polyketide natural products. Curr Opin Drug Discov Dev 4:215–228
Du L, Sanchez C, Shen B (2001) Hybrid peptide-polyketide natural products: biosynthesis and prospects towards engineering novel molecules. Metab Eng 3:78–95
Entian KD, Klein C (1993) Lantibiotika, eine Klasse ribosomal synthetisierter Peptid-Antibiotika. Naturwissenschaften 80:454–460
Felmingham D, Zhanel G, Hoban D (2001) Activity of the ketolide antibacterial telithromycin against typical community-acquired respiratory pathogens. J Antimicrob Chemother 48:33–42
Fernandez-Lopez S, Kim HS, Choi EC, Delgado M, Granja JR, Khasanov A, Kraehenbuehl A, Long G, Weinberger DA, Wilcoxen KM, Ghadiri R (2001) Antibacterial agents based on the cyclic d,l-α-peptide architecture. Nature 412:452–455
Finch RG (1996) Antibacterial activity of Quinupristin/Dalfopristin. Drugs 51[Suppl 1]:31–37
Floss HG (2001) Antibiotic synthesis: from natural to unnatural products. J Ind Microbiol Biotechnol 27:183–194
Gold HS, Moellering RC (1996) Antimicrobial drug resistance. Drug Therapy 335:1445–1453
Good AC, Krystek SR, Mason JS (2000) High throughput and virtual screening: core lead discovery technologies move towards integration: Drug Discov Today 5 [12 Suppl 1]:S61–S69
Hall RM, Collis CM (2001) Origins and evolution of antibiotic and multiple antibiotic resistance in bacteria. In: Lohner K (ed) Development of novel antimicrobial agents: emerging strategies. Horizon, Wymondham, Norfolk, UK, pp 17–30
Hancock REW, Patrzykat A (2002) Clinical development of cationic antimicrobial peptides: from natural to novel antibiotics. Curr Drug Targets Infect Disord 2:79–83
Hancock REW, Rozek A (2002) Role of membranes in the activities of antimicrobial cationic peptides. FEMS Microbiol Lett 10:143–149
Hancock REW, Scott MG (2000) The role of antimicrobial peptides in animal defences. Proc Natl Acad Sci USA 97:8856–8861
Haney SA, Alksne LE, Dunman PM, Murphy E, Projan SJ (2002) Genomics in anti-infective drug discovery—getting to an endgame. Curr Pharm Des 8:1099–1118
Heymann DL (2000) The urgency of a massive effort against infectious diseases. Statement before the United States House of Representatives. World Health Organisation, Geneva, Switzerland
Hiramatsu K (1998) The emergence of Staphylococcus aureus with reduced susceptibility to vancomycin in Japan. Am J Med 104:7S–10S
Hiramatsu K, Hanaki K, Ino T, Yabuta K, Oguri T, Tenover FC (1997) Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. J Antimicrob Chemother 40:135–146
Hollingshead SK, Briles DE (2001) Streptococcus pneumoniae: new tools for an old pathogen. Curr Opin Microbiol 4:71–77
Höltje HD, Stoll F, Ghosh R, Stahl G, Höltje M (2002) New methods in drug research. Pharm Ind 64:838–843
Hutchinson CR, Fujii I (1995) Polyketide synthase gene manipulation : a structure-function approach in engineering novel antibiotics. Annu Rev Microbiol 49:201
Jouenne T, Mor A, Bonato H, Junter GA (1998) Antibacterial activity of synthetic dermaseptins against growing and non-growing E. coli cultures. J Antimicrob Chemother 42:87–90
Kaneda T (1977) Fatty acids of the genus Bacillus: an example of branched chain preference. Bacteriol Rev 41:391–418
Katz L, Donadio S (1993) Polyketide synthesis: prospects for hybrid antibiotics. Annu Rev Microbiol 47:875–912
Kleinkauf H, von Döhren H (1995) Linking peptide and polyketide biosynthesis. J Antibiot 48:563–567
Lay JO (2001) MALDI-TOF mass spectrometry of bacteria. Mass Spectrom Rev 20:172–194
Leclercq JV (1996) Epidemiology and control of multiresistant enterococci. Drugs 52:47–49
Leclercq R (2001) Overcoming antimicrobial resistance: profile of a new ketolide antibacterial, telithromycin. J Antimicrob Chemother 48:9–23
Lehrer RI, Ganz T (2002) Cathelicidins: a family of endogenous antimicrobial peptides. Curr Opin Hematol 9:18–22
Leuenberger HGW, Matzinger PK, Wirz B (1999) Synthesis and metabolism of drugs by means of enzyme catalysed reactions. Chimia 53:536–540
Lohner K, Staudegger E (2001) Are we on the threshold of the post-antibiotic era? In: Lohner K (ed) Development of novel antimicrobial agents: emerging strategies. Horizon, Wymondham, Norfolk, UK, pp 1–16
Mankelow DP, Neilan BA (2000) Non-ribosomal peptide antibiotics. Expert Opin Ther Pat 10:1583–1591
Marahiel MA, Stachelhaus T, Mootz HD (1997) Modular peptide synthases involved in nonribosomal peptide synthesis. Chem Rev 97:2651–2673
Martin JF (1998) New aspects of genes and enzymes for β-lactam antibiotic synthesis. Appl Microbiol Biotechnol 50:1–15
McDaniel R, Katz L (2001) Genetic engineering of novel macrolide antibiotics. In: Lohner K (ed) Development of novel antimicrobial agents: emerging strategies. Horizon, Wymondham, Norfolk, UK, pp 45–60
Miller MB, Bassler BL (2001) Quorum sensing in bacteria. Annu Rev Microbiol 55:165–199
Mor A (2000) Peptide-based antibiotics: a potential answer to raging antimicrobial resistance. Drug Dev Res 50:440–447
Mor A, Hani K, Nicolas P (1994) The vertebrate peptide antibiotics dermaseptins have overlapping structural features but target specific organisms. J Biol Chem 269:31635–31641
Muhle SA, Tam JP (2001) Design of Gram-negative selective antimicrobial peptides. Biochemistry 40:5777–5785
Muhlemann K (2002) Mechanismen der Antibiotikaresistenz. Ther Umschau 59:5–10
Nicolaou KC, Boddy NC (2001) Behind enemy lines. Sci Am 284:46–53
Nielsen J (2001) Metabolic engineering. Appl Microbiol Biotechnol 55:263–285
Nilsson CL (2002) Bacterial proteomic and vaccine development. Am J Pharmacogenomics 2:59–65
Nissen-Meyer J, Nes IF (1997) Ribosomally synthesized antimicrobial peptides: their function, structure, biogenesis, and mechanism of action. Arch Microbiol 167:67–77
Pankuch GA, Visalli MA, Jacobs MR, Applebaum PC (1998) Susceptibilities of penicillin and erythromycin susceptible and resistant Pneumococci to HMR 3647 (RU 66647), a new ketolide, compared with susceptibilities to 17 other agents. Antimicrob Agents Chemother 42:624–630
Paul N, Rognan D (2002) ConsDock: a new program for the consensus analysis of protein-ligand interaction. Proteins Struct Funct Genet 47:521–533
Paulsen FP, Pufe T, Schaudig U, Held-Feindt J, Lehmann J, Schroder JM, Tillmann BN (2001) Detection of natural peptide antibiotics in human nasolacrimal ducts. Invest Ophthalmol Vis Sci 42:2157–2163
Pechère JC (1996) Streptogramins. Drugs 51 [Suppl 1]:13–19
Pfeifer BA, Khosla C (2001) Biosynthesis of polyketides in heterologous hosts. Microbiol Mol Biol Rev 3:106–118
Rowe-Magnus DA, Davies J, Mazel D (2002a) Impact of integrons and transposons on the evolution of resistance and virulence. In: Hacker J, Kaper JB (eds) Pathogenicity islands and the evolution of pathogenic microbes. Springer, Berlin Heidelberg New York, pp 167–188
Rowe-Magnus DA, Davies J, Mazel D (2002b) Impact of integrons and transposons on the evolution of resistance and virulence. Curr Top Microbiol Immunol 264:167–188
Rudert F (2000) Genomics and proteomics tools for the clinic. Curr Opin Mol Ther 2:633–642
Rusinko A, Young SS, Drewry DH, Gerritz SW (2002) Optimization of focused chemical libraries using recursive partioning. Comb Chem High Throughput Screen 5:125–133
Saiman L, Tabibi S, Starner TD, San-Gabriel P, Winokur PL, Hong-Peng J, McCray PB, Tack BF (2001) Cathelicidin peptides inhibit multiply antibiotic resistant pathogens from patients with cystic fibrosis. Antimicrob Agents Chemother 45:2838–2844
Schmidt FR (2002) Beta-lactam antibiotics: aspects of manufacture and therapy. In: Osiewacz HD (ed) The Mycota, vol X: industrial applications. Springer, Berlin Heidelberg New York, pp 69–91
Sieradzki K, Tomasz A (1996) A highly vancomycin resistant laboratory mutant of Staphylococcus aureus. FEMS Microbiol Lett 142:161–166
Sperandio V, Torres AG, Giron JA, Kaper JB (2001) Quorum sensing is a global regulatory mechanism in enterohemorrhagic Escherichia coli O157:H7. J Bacteriol 183:5187–5197
Staunton J, Wilkinson B (2001) Combinatorial biosynthesis of polyketides and nonribosomal peptides. Curr Opin Chem Biol 5:159–164
Stephenson J (2001) Researchers describe latest strategies to combat antibiotic resistant microbes. JAMA 285:2317–2318
Sun C, Wang H, Sun B, Peng XX (2000) Progress in the study of peptide antibiotics. Chin Pharmacol Bull 16:605–609
Sundberg SA (2000) High-throughput and ultra-high-throughput screening: solution- and cell-based approaches. Curr Opin Biotechnol 11:47–53
Tally FP, DeBruin F (2000) Development of daptomycin for Gram-positive infections. J Antimicrobial Chemotherapy 46:523–526
Tam JP, Lu YA, Yang YL (2002) Antimicrobial dendrimeric peptides. Eur J Biochem 269:923–932
Trauger JW, Walsh CT (2000) Heterologous expression in Escherichia coli of the first module of nonribosomal peptide synthase for chloroeremomycin, a vancomycin-type glycopeptide antibiotic. Proc Natl Acad USA 97:3112–3117
Trautmann M, Ruhnke M, Krsken M, Brauers J, Springsklee M, Marre R (1997) Quinupristin/Dalfopristin. Chemother J 6:31–42
Trnobranski PH (1998) Are we facing a "post-antibiotic era"?—a review of the literature regarding antimicrobial drug resistance. J Clin Nurs 7:392–400
Troxler R, von Grävenitz A, Funke G, Wiedemann B, Stock I (2000) Natural antibiotic susceptibility by Listeria species: L. grayi, L. innocua, L. ivanovii, L. monocytogenes, L. seeligeri and L. welshimeri strains. Clin Microbiol Infect 6:525–535
Vannuffel P, Cocito C (1996) Mechanism of action of streptogramins and macrolides. Drugs 51 [Suppl 1]:20–30
Versalovic J (2001) DNA-chip-based microbiology. Clin Microbiol Newslett 23:99–102
Vertesy, L, Aretz W, Decker H, Ehlers E, Kurz M, Schmidt FR, Knauf M, Kogler H (1999) Lipopetide calcium salts: process for their preparation and their use. European Patent 1068223
Vertesy L, Ehlers E, Kogler H, Kurz M, Meiwes J, Seibert G, Vogel M, Hammann P (2000) Friulimicins: novel lipopetide antibiotics with peptidoglycan synthesis inhibiting activity from Actinoplanes friulensis sp. nov. II. Isolation and structural characterization. J Antibiot 53:816–827
Waterman SR (2001) Bacterial genomics as a potential tool for discovering new antimicrobial agents. Am J Pharmacogenomics 1:263–269
Whittier S (2001) Update on the microbiology of cystic fibrosis: traditional and emerging pathogens. Clin Microbial Newslett 23:67–71
WHO Report on Infectious Diseases (2000) Overcoming antimicrobial resistance. World Health Organisation, Geneva, Switzerland
WHO Report on Infectious Diseases (2002) Scaling up the response to infectious diseases; a way out of poverty. World Health Organisation, Geneva, Switzerland
Wiedemann I, Breukink E, Van-Kraaij C, Kuipers OP, Bierbaum G, De Kruijff B, Sahl HG (2001) Specific binding of nisin to the peptidoglycan precursor lipid II combines pore formation and inhibition of cell wall biosynthesis for potent antibiotic activity. J Biol Chem 276:1772–1779
Wiesner A, Bogumi R (2002) Das ProteinChip-System in klinischer Forschung, Proteinisolierung und Proteinanalytik. Laborwelt, Biocom, April:10–17
Williams RJ, Heymann DL (1998) Containment of antibiotic resistance. Science 279:1153–1154
World Health Reports (1996–2001) World Health Organisation, Geneva, Switzerland
Yan H, Hancock REW (2001) Synergistic interactions between mammalian antimicrobial defense peptides. Antimicrob Agents Chemother 45:1558–1560
Zaks A (2001) Industrial biocatalysis. Curr Opin Chem Biol 5:130–136
Zasloff M (2001) The commercial development of the antimicrobial peptide Pexiganan. In: Lohner K (ed) Development of novel antimicrobial agents: emerging strategies. Horizon, Wymondham, Norfolk, UK, pp 262–272
Zhu J, Miller MB, Vance RE, Dziejman M, Bassler BL, Mekalanos JJ (2002) Quorum-sensing regulators control virulence gene expression in Vibrio cholerae. Proc Natl Acad Sci USA 99:3129–3134
Zmijewski MJ, Briggs B, Occolowitz J (1986) Role of branched chain fatty acid precursors in regulating factor profile in the biosynthesis of A21978 C complex. J Antibiot 39:1483–1485
Author information
Authors and Affiliations
Corresponding author
Additional information
The mentioned antibiotic preparations Augmentan, Klacid, Rulid, Synercid and Ketek are registered trade names of GlaxoSmithKline, Abbott and Aventis, respectively.
Rights and permissions
About this article
Cite this article
Schmidt, F.R. The challenge of multidrug resistance: actual strategies in the development of novel antibacterials. Appl Microbiol Biotechnol 63, 335–343 (2004). https://doi.org/10.1007/s00253-003-1344-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00253-003-1344-1