In recent years, the alarming increase of antibiotic resistance, compounded by the simultaneous decrease in development of new antibiotics, has created serious concerns for public health. Moreover, current antibiotics also target the beneficial commensal microbes (microbiota) that inhabit our body, sometimes with significant health consequences. The answer to the antibiotic crisis thus involves broad, creative efforts to develop new treatments for infectious agents. Here I discuss what can be learned from investigating microbial competition in vivo and how this knowledge can be utilized to devise new narrow-spectrum therapeutics that target bacterial pathogens while minimizing deleterious effects to the microbiota.
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Tan, S. Y. & Tatsumura, Y. Alexander Fleming (1881–1955): discoverer of penicillin. Singapore Med. J. 56, 366–367 (2015).
Bo, G. Giuseppe Brotzu and the discovery of cephalosporins. Clin. Microbiol. Infect. 6 (Suppl 3), 6–9 (2000).
Maffioli, S. I. et al. Antibacterial nucleoside-analog inhibitor of bacterial RNA polymerase. Cell 169, 1240–1248.e23 (2017).
Ling, L. L. et al. A new antibiotic kills pathogens without detectable resistance. Nature 517, 455–459 (2015).
Costa, K. C., Bergkessel, M., Saunders, S., Korlach, J. & Newman, D. K. Enzymatic degradation of phenazines can generate energy and protect sensitive organisms from toxicity. MBio 6, e01520–e15 (2015).
Costa, K. C., Glasser, N. R., Conway, S. J. & Newman, D. K. Pyocyanin degradation by a tautomerizing demethylase inhibits Pseudomonas aeruginosa biofilms. Science 355, 170–173 (2017).
The antibiotic alarm. Nature 495, 141 (2013).
Ventola, C. L. The antibiotic resistance crisis: part 1: causes and threats. P&T 40, 277–283 (2015).
Tacconelli, E. & Magrini, N. Global priority list of antibiotic-resistant bacteria to guide research discovery and development of new antibiotics. (World Health Organization, Geneva, 2017).
Queenan, A. M. & Bush, K. Carbapenemases: the versatile β-lactamases. Clin. Microbiol. Rev. 20, 440–458 (2007). table of contents.
Pogue, J. M., Mann, T., Barber, K. E. & Kaye, K. S. Carbapenem-resistant Acinetobacter baumannii: epidemiology, surveillance and management. Expert Rev. Anti Infect. Ther. 11, 383–393 (2013).
Meletis, G., Exindari, M., Vavatsi, N., Sofianou, D. & Diza, E. Mechanisms responsible for the emergence of carbapenem resistance in Pseudomonas aeruginosa. Hippokratia 16, 303–307 (2012).
Schwaber, M. J. & Carmeli, Y. Carbapenem-resistant Enterobacteriaceae: a potential threat. J. Am. Med. Assoc. 300, 2911–2913 (2008).
van Duin, D., Kaye, K. S., Neuner, E. A. & Bonomo, R. A. Carbapenem-resistant Enterobacteriaceae: a review of treatment and outcomes. Diagn. Microbiol. Infect. Dis. 75, 115–120 (2013).
Delcour, A. H. Outer membrane permeability and antibiotic resistance. Biochim. Biophys. Acta 1794, 808–816 (2009).
Hancock, R. E. The bacterial outer membrane as a drug barrier. Trends Microbiol. 5, 37–42 (1997).
Lewis, K. Platforms for antibiotic discovery. Nat. Rev. Drug Discov. 12, 371–387 (2013).
Clemente, J. C., Ursell, L. K., Parfrey, L. W. & Knight, R. The impact of the gut microbiota on human health: an integrative view. Cell 148, 1258–1270 (2012).
Hooper, L. V. & Gordon, J. I. Commensal host–bacterial relationships in the gut. Science 292, 1115–1118 (2001).
Sekirov, I., Russell, S. L., Antunes, L. C. & Finlay, B. B. Gut microbiota in health and disease. Physiol. Rev. 90, 859–904 (2010).
Ubeda, C. & Pamer, E. G. Antibiotics, microbiota, and immune defense. Trends Immunol. 33, 459–466 (2012).
Hibbing, M. E., Fuqua, C., Parsek, M. R. & Peterson, S. B. Bacterial competition: surviving and thriving in the microbial jungle. Nat. Rev. Microbiol. 8, 15–25 (2010).
Stubbendieck, R. M. & Straight, P. D. Multifaceted interfaces of bacterial competition. J. Bacteriol. 198, 2145–2155 (2016).
Dobson, A., Cotter, P. D., Ross, R. P. & Hill, C. Bacteriocin production: a probiotic trait? Appl. Environ. Microbiol. 78, 1–6 (2012).
Hassan, M., Kjos, M., Nes, I. F., Diep, D. B. & Lotfipour, F. Natural antimicrobial peptides from bacteria: characteristics and potential applications to fight against antibiotic resistance. J. Appl. Microbiol. 113, 723–736 (2012).
Hayes, C. S., Koskiniemi, S., Ruhe, Z. C., Poole, S. J. & Low, D. A. Mechanisms and biological roles of contact-dependent growth inhibition systems. Cold Spring Harb. Perspect. Med. 4, a010025 (2014).
Russell, A. B., Peterson, S. B. & Mougous, J. D. Type VI secretion system effectors: poisons with a purpose. Nat. Rev. Microbiol. 12, 137–148 (2014).
Aoki, S. K. et al. A widespread family of polymorphic contact-dependent toxin delivery systems in bacteria. Nature 468, 439–442 (2010).
Aoki, S. K. et al. Contact-dependent inhibition of growth in Escherichia coli. Science 309, 1245–1248 (2005).
Mougous, J. D. et al. A virulence locus of Pseudomonas aeruginosa encodes a protein secretion apparatus. Science 312, 1526–1530 (2006).
Alteri, C.J. & Mobley, H.L. The versatile type VI secretion system. in Virulence Mechanisms of Bacterial Pathogens, 5th edn. (eds. Kudva, I. et al.) 337–356 (ASM Press, Washington DC, 2016).
Xavier, K. B. & Bassler, B. L. Interference with AI-2-mediated bacterial cell–cell communication. Nature 437, 750–753 (2005).
Chen, F., Gao, Y., Chen, X., Yu, Z. & Li, X. Quorum quenching enzymes and their application in degrading signal molecules to block quorum sensing-dependent infection. Int. J. Mol. Sci. 14, 17477–17500 (2013).
LaSarre, B. & Federle, M. J. Exploiting quorum sensing to confuse bacterial pathogens. Microbiol. Mol. Biol. Rev. 77, 73–111 (2013).
Curtis, M. M. et al. QseC inhibitors as an antivirulence approach for Gram-negative pathogens. MBio 5, e02165 (2014).
O’Loughlin, C. T. et al. A quorum-sensing inhibitor blocks Pseudomonas aeruginosa virulence and biofilm formation. Proc. Natl Acad. Sci. USA 110, 17981–17986 (2013).
Vraspir, J. M. & Butler, A. Chemistry of marine ligands and siderophores. Ann. Rev. Mar. Sci. 1, 43–63 (2009).
Cassat, J. E. & Skaar, E. P. Iron in infection and immunity. Cell host & microbe 13, 509–519 (2013).
Crosa, J. H. & Walsh, C. T. Genetics and assembly line enzymology of siderophore biosynthesis in bacteria. Microbiol. Mol. Biol. Rev. 66, 223–249 (2002).
Traxler, M. F., Seyedsayamdost, M. R., Clardy, J. & Kolter, R. Interspecies modulation of bacterial development through iron competition and siderophore piracy. Mol. Microbiol. 86, 628–644 (2012).
Chu, B. C. et al. Siderophore uptake in bacteria and the battle for iron with the host; a bird’s eye view. Biometals 23, 601–611 (2010).
Kamada, N. et al. Regulated virulence controls the ability of a pathogen to compete with the gut microbiota. Science 336, 1325–1329 (2012).
Dethlefsen, L. & Relman, D. A. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc. Natl Acad. Sci. USA 108 (Suppl 1), 4554–4561 (2011).
FAO/WHO. Expert consultation on evaluation of health and nutritional properties of probiotics in food including milk powder with live lactic acid bacteria. (Food and Agriculture Organization/World Health Organization, Cordoba, Argentina, 2001).
Behnsen, J., Deriu, E., Sassone-Corsi, M. & Raffatellu, M. Probiotics: properties, examples, and specific applications. Cold Spring Harb. Perspect. Med. 3, a010074 (2013).
Yan, F. & Polk, D. B. Probiotics and immune health. Curr. Opin. Gastroenterol. 27, 496–501 (2011).
Servin, A. L. Antagonistic activities of lactobacilli and bifidobacteria against microbial pathogens. FEMS Microbiol. Rev. 28, 405–440 (2004).
Cotter, P. D., Hill, C. & Ross, R. P. Bacteriocins: developing innate immunity for food. Nat. Rev. Microbiol. 3, 777–788 (2005).
Corr, S. C. et al. Bacteriocin production as a mechanism for the antiinfective activity of Lactobacillus salivarius UCC118. Proc. Natl Acad. Sci. USA 104, 7617–7621 (2007).
Riboulet-Bisson, E. et al. Effect of Lactobacillus salivarius bacteriocin Abp118 on the mouse and pig intestinal microbiota. PLoS One 7, e31113 (2012).
Kommineni, S. et al. Bacteriocin production augments niche competition by enterococci in the mammalian gastrointestinal tract. Nature 526, 719–722 (2015).
Kluytmans, J., van Belkum, A. & Verbrugh, H. Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks. Clin. Microbiol. Rev. 10, 505–520 (1997).
Gong, J. Q. et al. Skin colonization by Staphylococcus aureus in patients with eczema and atopic dermatitis and relevant combined topical therapy: a double-blind multicentre randomized controlled trial. Br. J. Dermatol. 155, 680–687 (2006).
Nakatsuji, T. et al. Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Sci. Transl. Med. 9, eaah4680 (2017).
Zipperer, A. et al. Human commensals producing a novel antibiotic impair pathogen colonization. Nature 535, 511–516 (2016).
Geisinger, E., Muir, T. W. & Novick, R. P. agr receptor mutants reveal distinct modes of inhibition by staphylococcal autoinducing peptides. Proc. Natl Acad. Sci. USA 106, 1216–1221 (2009).
Paharik, A. E. et al. Coagulase-negative staphylococcal strain prevents Staphylococcus aureus colonization and skin infection by blocking quorum sensing. Cell Host Microbe 22, 746–756.e5 (2017).
Abt, M. C., McKenney, P. T. & Pamer, E. G. Clostridium difficile colitis: pathogenesis and host defence. Nat. Rev. Microbiol. 14, 609–620 (2016).
Sorg, J. A. & Sonenshein, A. L. Inhibiting the initiation of Clostridium difficile spore germination using analogs of chenodeoxycholic acid, a bile acid. J. Bacteriol. 192, 4983–4990 (2010).
Buffie, C. G. et al. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature 517, 205–208 (2015).
Theriot, C. M. et al. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nat. Commun. 5, 3114 (2014).
Reeves, A. E., Koenigsknecht, M. J., Bergin, I. L. & Young, V. B. Suppression of Clostridium difficile in the gastrointestinal tracts of germfree mice inoculated with a murine isolate from the family Lachnospiraceae. Infect. Immun. 80, 3786–3794 (2012).
Lawley, T. D. et al. Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice. PLoS Pathog. 8, e1002995 (2012).
Round, J. L. et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977 (2011).
Round, J. L. & Mazmanian, S. K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204–12209 (2010).
Lee, S. M. et al. Bacterial colonization factors control specificity and stability of the gut microbiota. Nature 501, 426–429 (2013).
Wu, S. et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat. Med. 15, 1016–1022 (2009).
Choi, V. M. et al. Activation of Bacteroides fragilis toxin by a novel bacterial protease contributes to anaerobic sepsis in mice. Nat. Med. 22, 563–567 (2016).
Zitomersky, N. L., Coyne, M. J. & Comstock, L. E. Longitudinal analysis of the prevalence, maintenance, and IgA response to species of the order Bacteroidales in the human gut. Infect. Immun. 79, 2012–2020 (2011).
Chatzidaki-Livanis, M., Geva-Zatorsky, N. & Comstock, L. E. Bacteroides fragilis type VI secretion systems use novel effector and immunity proteins to antagonize human gut Bacteroidales species. Proc. Natl Acad. Sci. USA 113, 3627–3632 (2016).
Hecht, A. L. et al. Strain competition restricts colonization of an enteric pathogen and prevents colitis. EMBO Rep. 17, 1281–1291 (2016).
Russell, A. B. et al. A type VI secretion–related pathway in Bacteroidetes mediates interbacterial antagonism. Cell Host Microbe 16, 227–236 (2014).
Wexler, A. G. et al. Human symbionts inject and neutralize antibacterial toxins to persist in the gut. Proc. Natl Acad. Sci. USA 113, 3639–3644 (2016).
Winter, S. E. et al. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science 339, 708–711 (2013).
Winter, S. E. & Bäumler, A. J. Dysbiosis in the inflamed intestine: chance favors the prepared microbe. Gut Microbes 5, 71–73 (2014).
Behnsen, J. et al. The cytokine IL-22 promotes pathogen colonization by suppressing related commensal bacteria. Immunity 40, 262–273 (2014).
Deriu, E. et al. Probiotic bacteria reduce Salmonella typhimurium intestinal colonization by competing for iron. Cell Host Microbe 14, 26–37 (2013).
Sassone-Corsi, M. et al. Siderophore-based immunization strategy to inhibit growth of enteric pathogens. Proc. Natl Acad. Sci. USA 113, 13462–13467 (2016).
Mike, L. A., Smith, S. N., Sumner, C. A., Eaton, K. A. & Mobley, H. L. Siderophore vaccine conjugates protect against uropathogenic Escherichia coli urinary tract infection. Proc. Natl Acad. Sci. USA 113, 13468–13473 (2016).
Ilott, N. E. et al. Defining the microbial transcriptional response to colitis through integrated host and microbiome profiling. ISME J. 10, 2389–2404 (2016).
Zhu, W. et al. Precision editing of the gut microbiota ameliorates colitis. Nature 553, 208–211 (2018).
Sassone-Corsi, M. et al. Microcins mediate competition among Enterobacteriaceae in the inflamed gut. Nature 540, 280–283 (2016).
Rebuffat, S. Microcin in action: amazing defence strategies of Enterobacteria. Biochem. Soc. Trans. 40, 1456–1462 (2012).
Duquesne, S., Destoumieux-Garzón, D., Peduzzi, J. & Rebuffat, S. Microcins, gene-encoded antibacterial peptides from enterobacteria. Nat. Prod. Rep. 24, 708–734 (2007).
Baquero, F. & Moreno, F. The microcins. FEMS Microbiol. Lett. 23, 117–124 (1978).
Asensio, C., Pérez-Díaz, J. C., Martinez, M. C. & Baquero, F. A new family of low molecular weight antibiotics from enterobacteria. Biochem. Biophys. Res. Commun. 69, 7–14 (1976).
Thomas, X. et al. Siderophore peptide, a new type of post-translationally modified antibacterial peptide with potent activity. J. Biol. Chem. 279, 28233–28242 (2004).
Vassiliadis, G., Destoumieux-Garzon, D. & Peduzzi, J. in Prokaryotic Antimicrobial Peptides (eds. Drider, D. & Rebuffat, S.) (Springer, New York, 2011).
Braun, V., Patzer, S. I. & Hantke, K. Ton-dependent colicins and microcins: modular design and evolution. Biochimie 84, 365–380 (2002).
Zheng, T. & Nolan, E. M. Enterobactin-mediated delivery of β-lactam antibiotics enhances antibacterial activity against pathogenic Escherichia coli. J. Am. Chem. Soc. 136, 9677–9691 (2014).
Chairatana, P., Zheng, T. & Nolan, E. M. Targeting virulence: salmochelin modification tunes the antibacterial activity spectrum of β-lactams for pathogen-selective killing of Escherichia coli. Chem. Sci. 6, 4458–4471 (2015).
Tillotson, G. S. Trojan horse antibiotics—a novel way to circumvent Gram-negative bacterial resistance? Infect. Dis. (Auckl.) 9, 45–52 (2016).
Mislin, G. L. & Schalk, I. J. Siderophore-dependent iron uptake systems as gates for antibiotic Trojan horse strategies against Pseudomonas aeruginosa. Metallomics 6, 408–420 (2014).
Ji, C., Juárez-Hernández, R. E. & Miller, M. J. Exploiting bacterial iron acquisition: siderophore conjugates. Future Med. Chem. 4, 297–313 (2012).
Tomaras, A. P. et al. Adaptation-based resistance to siderophore-conjugated antibacterial agents by Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 57, 4197–4207 (2013).
Kim, A. et al. Pharmacodynamic profiling of a siderophore-conjugated monocarbam in Pseudomonas aeruginosa: assessing the risk for resistance and attenuated efficacy. Antimicrob. Agents Chemother. 59, 7743–7752 (2015).
Kohira, N. et al. In vitro antimicrobial activity of a siderophore cephalosporin, S-649266, against Enterobacteriaceae clinical isolates, including carbapenem-resistant strains. Antimicrob. Agents Chemother. 60, 729–734 (2015).
Ito, A. et al. Siderophore cephalosporin cefiderocol utilizes ferric iron transporter systems for antibacterial activity against Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 60, 7396–7401 (2016).
Ito, A. et al. In vitro antibacterial properties of cefiderocol, a novel siderophore cephalosporin, against Gram-negative bacteria. Antimicrob. Agents Chemother. 62, e01454–17 (2018).
Charlop-Powers, Z. et al. Urban park soil microbiomes are a rich reservoir of natural product biosynthetic diversity. Proc. Natl Acad. Sci. USA 113, 14811–14816 (2016).
Nothias, L. F., Knight, R. & Dorrestein, P. C. Antibiotic discovery is a walk in the park. Proc. Natl Acad. Sci. USA 113, 14477–14479 (2016).
Donia, M. S. & Fischbach, M. A. HUMAN MICROBIOTA. Small molecules from the human microbiota. Science 349, 1254766 (2015).
Mousa, W. K., Athar, B., Merwin, N. J. & Magarvey, N. A. Antibiotics and specialized metabolites from the human microbiota. Nat. Prod. Rep. 34, 1302–1331 (2017).
Medema, M. H. & Fischbach, M. A. Computational approaches to natural product discovery. Nat. Chem. Biol. 11, 639–648 (2015).
Gonzalez, D. J. et al. Microbial competition between Bacillus subtilis and Staphylococcus aureus monitored by imaging mass spectrometry. Microbiology 157, 2485–2492 (2011).
Cogen, A. L., Nizet, V. & Gallo, R. L. Skin microbiota: a source of disease or defence? Br. J. Dermatol. 158, 442–455 (2008).
Donaldson, G. P., Lee, S. M. & Mazmanian, S. K. Gut biogeography of the bacterial microbiota. Nat. Rev. Microbiol. 14, 20–32 (2016).
Buffie, C. G. & Pamer, E. G. Microbiota-mediated colonization resistance against intestinal pathogens. Nat. Rev. Immunol. 13, 790–801 (2013).
Lawley, T. D. & Walker, A. W. Intestinal colonization resistance. Immunology 138, 1–11 (2013).
Sassone-Corsi, M. & Raffatellu, M. No vacancy: how beneficial microbes cooperate with immunity to provide colonization resistance to pathogens. J. Immunol. 194, 4081–4087 (2015).
M.R. would like to thank S.P. Nuccio for helpful discussions and editing of the manuscript. M.R. is supported by NIH Public Health Service Grants AI114625, AI126277, AI121928, and AI126465. M.R. holds an Investigator in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund.
The author has a patent application related to siderophore-conjugate immunization.
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Raffatellu, M. Learning from bacterial competition in the host to develop antimicrobials. Nat Med 24, 1097–1103 (2018). https://doi.org/10.1038/s41591-018-0145-0
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