Lewis, K. The science of antibiotic discovery. Cell 181, 29–45 (2020).
Tacconelli, E. et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect. Dis. 18, 318–327 (2018).
Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 399, 629–655 (2022).
Ramos-Castaneda, J. A. et al. Mortality due to KPC carbapenemase-producing Klebsiella pneumoniae infections: systematic review and meta-analysis: mortality due to KPC Klebsiella pneumoniae infections. J. Infect. 76, 438–448 (2018).
Xu, L., Sun, X. & Ma, X. Systematic review and meta-analysis of mortality of patients infected with carbapenem-resistant Klebsiella pneumoniae. Ann. Clin. Microbiol. Antimicrob. 16, 18 (2017).
Zgurskaya, H. I., Rybenkov, V. V., Krishnamoorthy, G. & Leus, I. V. Trans-envelope multidrug efflux pumps of Gram-negative bacteria and their synergism with the outer membrane barrier. Res. Microbiol. 169, 351–356 (2018).
Staley, J. T. & Konopka, A. Measurement of in situ activities of nonphotosynthetic microorganisms in aquatic and terrestrial habitats. Annu. Rev. Microbiol. 39, 321–346 (1985).
D’Onofrio, A. et al. Siderophores from neighboring organisms promote the growth of uncultured bacteria. Chem. Biol. 17, 254–264 (2010).
Fenn, K. et al. Quinones are growth factors for the human gut microbiota. Microbiome 5, 161 (2017).
Strandwitz, P. et al. GABA-modulating bacteria of the human gut microbiota. Nat. Microbiol. 4, 396–403 (2019).
Ling, L. L. et al. A new antibiotic kills pathogens without detectable resistance. Nature 517, 455–459 (2015). This paper describes the discovery of teixobactin from an uncultured bacterium.
Shukla, R. et al. An antibiotic from an uncultured bacterium binds to an immutable target. Cell 186, 4059–4073.e4027 (2023).
Pantel, L. et al. Odilorhabdins, antibacterial agents that cause miscoding by binding at a new ribosomal site. Mol. Cell 70, 83–94 e87 (2018).
Imai, Y. et al. A new antibiotic selectively kills Gram-negative pathogens. Nature 576, 459–464 (2019).
Imai, Y. et al. Evybactin is a DNA gyrase inhibitor that selectively kills Mycobacterium tuberculosis. Nat. Chem. Biol. 18, 1236–1244 (2022). This paper describes the discovery of darobactins that target BamA in the outer membrane of Gram-negative bacteria.
Miller, R. D. et al. Computational identification of a systemic antibiotic for gram-negative bacteria. Nat. Microbiol. 7, 1661–1672 (2022).
Shahsavari, N. et al. A silent operon of Photorhabdus luminescens encodes a prodrug mimic of GTP. mBio 13, e0070022 (2022).
Libis, V. et al. Multiplexed mobilization and expression of biosynthetic gene clusters. Nat. Commun. 13, 5256 (2022). This paper describes an approach for efficient cloning of environmental DNA for the expression of BGCs.
Gavriilidou, A. et al. Compendium of specialized metabolite biosynthetic diversity encoded in bacterial genomes. Nat. Microbiol. 7, 726–735 (2022). This study catalogues BGCs from sequenced genomes and links them to taxonomy and biogeography.
O’Shea, R. & Moser, H. E. Physicochemical properties of antibacterial compounds: Implications for drug discovery. J. Med. Chem. 51, 2871–2878 (2008).
Richter, M. F. et al. Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature 545, 299–304 (2017). This study provides rules for compound penetration into Gram-negative bacteria.
Mehla, J. et al. Predictive rules of efflux inhibition and avoidance in Pseudomonas aeruginosa. mBio 12, e02785–20 (2021). This study analyses physico-chemical properties of compounds that enable penetration into P. aeruginosa, and synthesis of MDR inhibitors.
Zhao, S. et al. Defining new chemical space for drug penetration into Gram-negative bacteria. Nat. Chem. Biol. 16, 1293–1302 (2020).
Mansbach, R. A. et al. Machine learning algorithm identifies an antibiotic vocabulary for permeating Gram-negative bacteria. J. Chem. Inf. Model. 60, 2838–2847 (2020).
Geddes, E. J. et al. Porin-independent accumulation in Pseudomonas enables antibiotic discovery. Nature 624, 145–153 (2023).
Parker, E. N. et al. Implementation of permeation rules leads to a FabI inhibitor with activity against Gram-negative pathogens. Nat. Microbiol. 5, 67–75 (2020).
Durand-Reville, T. F. et al. Rational design of a new antibiotic class for drug-resistant infections. Nature 597, 698–702 (2021).
Srinivas, N. et al. Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa. Science 327, 1010–1013 (2010).
Luther, A. et al. Chimeric peptidomimetic antibiotics against Gram-negative bacteria. Nature 576, 452–458 (2019).
Pahil, K. S. et al. A new antibiotic traps lipopolysaccharide in its intermembrane transporter. Nature 625, 572–577 (2024).
Zampaloni, C. et al. A novel antibiotic class targeting the lipopolysaccharide transporter. Nature 625, 566–571 (2024).
Fleming, A. On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae. Br. J. Exp. Pathol. 10, 226 (1929).
Mora-Ochomogo, M. & Lohans, C. T. β-Lactam antibiotic targets and resistance mechanisms: from covalent inhibitors to substrates. RSC Med. Chem. 12, 1623–1639 (2021).
Silver, L. L. Multi-targeting by monotherapeutic antibacterials. Nat. Rev. Drug Discov. 6, 41–55 (2007).
Reading, C. & Cole, M. Clavulanic acid: a beta-lactamase-inhibiting beta-lactam from Streptomyces clavuligerus. Antimicrob. Agents Chemother. 11, 852–857 (1977).
Levasseur, P. et al. Efficacy of a ceftazidime–avibactam combination in a murine model of septicemia caused by Enterobacteriaceae species producing ampc or extended-spectrum β-lactamases. Antimicrob. Agents Chemother. 58, 6490–6495 (2014).
Wunderink, R. G. et al. Effect and safety of meropenem-vaborbactam versus best-available therapy in patients with carbapenem-resistant Enterobacteriaceae infections: The TANGO II randomized clinical trial. Infect. Dis. Ther. 7, 439–455 (2018).
Lewis, K. & Ausubel, F. M. Prospects for plant-derived antibacterials. Nat. Biotechnol. 24, 1504–1507 (2006).
Stermitz, F. R., Lorenz, P., Tawara, J. N., Zenewicz, L. A. & Lewis, K. Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor. Proc. Natl Acad. Sci. USA 97, 1433–1437 (2000).
Moniruzzaman, M. et al. Analysis of orthogonal efflux and permeation properties of compounds leads to the discovery of new efflux pump inhibitors. ACS Infect. Dis. 8, 2149–2160 (2022).
Dominguez-Bello, M. G., Godoy-Vitorino, F., Knight, R. & Blaser, M. J. Role of the microbiome in human development. Gut 68, 1108–1114 (2019).
Schnizlein, M. K. & Young, V. B. Capturing the environment of the Clostridioides difficile infection cycle. Nat. Rev. Gastroenterol. Hepatol. 19, 508–520 (2022).
Anthony, W. E. et al. Acute and persistent effects of commonly used antibiotics on the gut microbiome and resistome in healthy adults. Cell Rep. 39, 110649 (2022).
Feuerstadt, P. et al. SER-109, an oral microbiome therapy for recurrent Clostridioides difficile infection. N. Engl. J. Med. 386, 220–229 (2022). This paper describes the introduction of a new type of ‘drug’—an assemblage of clostridial spores for the treatment of C. difficile infection.
Lopetuso, L. R., Scaldaferri, F., Petito, V. & Gasbarrini, A. Commensal clostridia: leading players in the maintenance of gut homeostasis. Gut Pathog. 5, 23 (2013).
Mikusova, K., Slayden, R. A., Besra, G. S. & Brennan, P. J. Biogenesis of the mycobacterial cell wall and the site of action of ethambutol. Antimicrob. Agents Chemother. 39, 2484–2489 (1995).
Chahine, E. B., Karaoui, L. R. & Mansour, H. Bedaquiline: a novel diarylquinoline for multidrug-resistant tuberculosis. Ann. Pharmacother. 48, 107–115 (2014).
Diallo, D. et al. Antituberculosis therapy and gut microbiota: review of potential host microbiota directed-therapies. Front. Cell. Infect. Microbiol. 11, 673100 (2021).
Quigley, J. et al. Novel antimicrobials from uncultured bacteria acting against Mycobacterium tuberculosis. mBio 11, e01516–e01520 (2020).
Motiwala, T., Mthethwa, Q., Achilonu, I. & Khoza, T. ESKAPE pathogens: looking at Clp ATPases as potential drug targets. Antibiotics 11, 1218 (2022).
Rempel, S. et al. A mycobacterial ABC transporter mediates the uptake of hydrophilic compounds. Nature 580, 409–412 (2020).
Leimer, N. et al. A selective antibiotic for Lyme disease. Cell 184, 5405–5418.e5416 (2021). This paper describes the identification of an antibiotic for selective action against B. burgdorferi.
Polikanov, Y. S., Melnikov, S. V., Soll, D. & Steitz, T. A. Structural insights into the role of rRNA modifications in protein synthesis and ribosome assembly. Nat. Struct. Mol. Biol. 22, 342–344 (2015).
Chatterjee, A. N. & Perkins, H. R. Compounds formed between nucleotides related to the biosynthesis of bacterial cell wall and vancomycin. Biochem. Biophys. Res. Commun. 24, 489–494 (1966).
Munch, D. & Sahl, H. G. Structural variations of the cell wall precursor lipid II in Gram-positive bacteria – Impact on binding and efficacy of antimicrobial peptides. Biochim. Biophys. Acta 1848, 3062–3071 (2015).
Leclercq, R., Derlot, E., Duval, J. & Courvalin, P. Plasmid-mediated resistance to vancomycin and teicoplanin in Enterococcus faecium. N. Engl. J. Med. 319, 157–161 (1988).
Marshall, C. G., Broadhead, G., Leskiw, B. K. & Wright, G. D. d-Ala–d-Ala ligases from glycopeptide antibiotic-producing organisms are highly homologous to the enterococcal vancomycin-resistance ligases VanA and VanB. Proc. Natl Acad. Sci. USA 94, 6480–6483 (1997).
Shukla, R. et al. Teixobactin kills bacteria by a two-pronged attack on the cell envelope. Nature 608, 390–396 (2022).
Shukla, R. et al. An antibiotic from an uncultured bacterium binds to an immutable target. Cell 186, 4059–4073 (2023).
Homma, T. et al. Dual targeting of cell wall precursors by teixobactin leads to cell lysis. Antimicrob. Agents Chemother. 60, 6510–6517 (2016).
Schatz, A., Bugie, E. & Waksman, S. A. Streptomycin, a substance exhibiting antibiotic activity against Gram-positive and Gram-negative bacteria. Proc. Soc. Exp. Biol. Med. 55, 66–69 (1944).
Wilson, D. N. Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nat. Rev. Microbiol. 12, 35–48 (2014).
Aguirre Rivera, J. et al. Real-time measurements of aminoglycoside effects on protein synthesis in live cells. Proc. Natl Acad. Sci. USA 118, e2013315118 (2021).
Andersson, D. I., Bohman, K., Isaksson, L. A. & Kurland, C. G. Translation rates and misreading characteristics of rpsD mutants in Escherichia coli. Mol. Genetics Genomics 187, 467–472 (1982).
Wohlgemuth, I. et al. Translation error clusters induced by aminoglycoside antibiotics. Nat. Commun. 12, 1830 (2021). This study reveals the basis of killing by aminoglycosides—the introduction of strings of errors into nascent proteins.
Tokuriki, N. & Tawfik, D. S. Stability effects of mutations and protein evolvability. Curr. Opin. Struct. Biol. 19, 596–604 (2009).
Kling, A. et al. Targeting DnaN for tuberculosis therapy using novel griselimycins. Science 348, 1106–1112 (2015).
Lewis, K. (ed.) Persister Cells and Infectious Disease (Springer Nature, 2019).
Dorr, T., Vulic, M. & Lewis, K. Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli. PLoS Biol. 8, e1000317 (2010).
Berghoff, B. A., Hoekzema, M., Aulbach, L. & Wagner, E. G. Two regulatory RNA elements affect TisB-dependent depolarization and persister formation. Mol. Microbiol. 103, 1020–1033 (2017).
Romilly, C., Deindl, S. & Wagner, E. G. H. The ribosomal protein S1-dependent standby site in tisB mRNA consists of a single-stranded region and a 5′ structure element. Proc. Natl Acad. Sci. USA 116, 15901–15906 (2019).
Schumacher, M. A. et al. HipBA–promoter structures reveal the basis of heritable multidrug tolerance. Nature 524, 59–64 (2015).
Manuse, S. et al. Bacterial persisters are a stochastically formed subpopulation of low-energy cells. PLoS Biol. 19, e3001194 (2021).
Quigley, J. & Lewis, K. Noise in a metabolic pathway leads to persister formation in Mycobacterium tuberculosis. Microbiol. Spectr. 10, e0294822 (2022).
Fleck, L. E. et al. A screen for and validation of prodrug antimicrobials. Antimicrob. Agents Chemother. 58, 1410–1419 (2014).
Goodreid, J. D. et al. Total synthesis and antibacterial testing of the A54556 cyclic acyldepsipeptides isolated from Streptomyces hawaiiensis. J. Nat. Prod. 77, 2170–2181 (2014).
Thomy, D. et al. The ADEP biosynthetic gene cluster in Streptomyces hawaiiensis NRRL 15010 reveals an accessory clpP gene as a novel antibiotic resistance factor. Appl. Environ. Microbiol. 85, e01292–19 (2019).
Brotz-Oesterhelt, H. et al. Dysregulation of bacterial proteolytic machinery by a new class of antibiotics. Nat. Med. 11, 1082–1087 (2005). This paper describes the discovery of the mechanism of killing by ADEP: dysregulation of the bacterial protease ClpP.
Olivares, A. O., Nager, A. R., Iosefson, O., Sauer, R. T. & Baker, T. A. Mechanochemical basis of protein degradation by a double-ring AAA+ machine. Nat. Struct. Mol. Biol. 21, 871–875 (2014).
Vahidi, S. et al. Reversible inhibition of the ClpP protease via an N-terminal conformational switch. Proc. Natl Acad. Sci. USA 115, E6447–E6456 (2018).
Griffith, E. C. et al. Ureadepsipeptides as ClpP Activators. ACS Infect. Dis. 5, 1915–1925 (2019).
Malik, I. T. et al. Functional characterisation of ClpP mutations conferring resistance to acyldepsipeptide antibiotics in firmicutes. ChemBioChem 21, 1997–2012 (2020).
Gatsogiannis, C., Balogh, D., Merino, F., Sieber, S. A. & Raunser, S. Cryo-EM structure of the ClpXP protein degradation machinery. Nat. Struct. Mol. Biol. 26, 946–954 (2019).
Ripstein, Z. A., Vahidi, S., Houry, W. A., Rubinstein, J. L. & Kay, L. E. A processive rotary mechanism couples substrate unfolding and proteolysis in the ClpXP degradation machinery. eLife 9, e52158 (2020).
Fei, X. et al. Structures of the ATP-fueled ClpXP proteolytic machine bound to protein substrate. eLife 9, e52774 (2020).
Sass, P. et al. Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ. Proc. Natl Acad. Sci. USA 108, 17474–17479 (2011).
Silber, N., Mayer, C., Matos de Opitz, C. L. & Sass, P. Progression of the late-stage divisome is unaffected by the depletion of the cytoplasmic FtsZ pool. Commun. Biol. 4, 270 (2021).
Conlon, B. P. et al. Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature 503, 365–370 (2013). This paper describes the anti-persister activity of ADEP.
Mroue, N. et al. Pharmacodynamics of ClpP-activating antibiotic combinations against Gram-positive pathogens. Antimicrob. Agents Chemother. 64, e01554-19 (2019).
Brown Gandt, A. et al. In vivo and in vitro effects of a ClpP-activating antibiotic against vancomycin-resistant enterococci. Antimicrob. Agents Chemother. 62, e00424-18 (2018).
Brotz-Oesterhelt, H. & Vorbach, A. Reprogramming of the caseinolytic protease by ADEP antibiotics: molecular mechanism, cellular consequences, therapeutic potential. Front. Mol. Biosci. 8, 690902 (2021).
Frees, D., Gerth, U. & Ingmer, H. Clp chaperones and proteases are central in stress survival, virulence and antibiotic resistance of Staphylococcus aureus. Int. J. Med. Microbiol. 304, 142–149 (2014).
Illigmann, A., Thoma, Y., Pan, S., Reinhardt, L. & Brotz-Oesterhelt, H. Contribution of the Clp protease to bacterial survival and mitochondrial homoeostasis. Microb. Physiol. 31, 260–279 (2021).
Schuster, M. et al. Peptidomimetic antibiotics disrupt the lipopolysaccharide transport bridge of drug-resistant Enterobacteriaceae. Sci. Adv. 9, eadg3683 (2023).
Nguyen, H. et al. Characterization of a radical SAM oxygenase for the ether crosslinking in darobactin biosynthesis. J. Am. Chem. Soc. 144, 18876–18886 (2022).
Kaur, H. et al. The antibiotic darobactin mimics a β-strand to inhibit outer membrane insertase. Nature 593, 125–129 (2021).
Groß, S. et al. Improved broad-spectrum antibiotics against Gram-negative pathogens via darobactin biosynthetic pathway engineering. Chem. Sci. 12, 11882–11893 (2021).
Seyfert, C. E. et al. Darobactins exhibiting superior antibiotic activity by Cryo-EM structure guided biosynthetic engineering. Angew. Chem. Int. Ed. Engl. 62, e202214094 (2022).
Lin, Y. C. et al. Atroposelective total synthesis of darobactin A. J. Am. Chem. Soc. 144, 14458–14462 (2022).
Nesic, M. et al. Total synthesis of darobactin A. J. Am. Chem. Soc. 144, 14026–14030 (2022).
Tan, Y. S., Lane, D. P. & Verma, C. S. Stapled peptide design: principles and roles of computation. Drug Discov. Today 21, 1642–1653 (2016).
Maeda, K., Osato, T. & Umezawa, H. A new antibiotic, azomycin. J. Antibiot. 6, 182 (1953).
Nakamura, S. Structure of azomycin, a new antibiotic. Pharm. Bull. 3, 379–383 (1955).
Shoji, J. H. et al. Isolation of azomycin from Pseudomonas fluorescens. J. Antibiot. 42, 1513–1514 (1989).
Gupta, R. et al. Functionalized nitroimidazole scaffold construction and their pharmaceutical applications: a 1950–2021 comprehensive overview. Pharmaceuticals 15, 561 (2022).
Goldstein, B. P. et al. The mechanism of action of nitro-heterocyclic antimicrobial drugs. Metabolic activation by micro-organisms. J. Gen. Microbiol. 100, 283–298 (1977).
Miller, M. J. & Liu, R. Design and syntheses of new antibiotics inspired by nature’s quest for iron in an oxidative climate. Acc. Chem. Res. 54, 1646–1661 (2021).
Sato, T. & Yamawaki, K. Cefiderocol: discovery, chemistry, and in vivo profiles of a novel siderophore cephalosporin. Clin. Infect. Dis. 69, S538–S543 (2019). This paper describes the creation of an approved chimeric antibiotic utilizing a siderophore moiety for penetration into the cell.
Broder, S. The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic. Antiviral Res. 85, 1–18 (2010).
Sanger, F., Nicklen, S. & Coulson, A. R. DNA sequencing with chain-terminating inhibitors. Proc. Natl Acad. Sci. USA 74, 5463–5467 (1977).
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).
Cao, Y. et al. Commensal microbiota from patients with inflammatory bowel disease produce genotoxic metabolites. Science 378, eabm3233 (2022).
Lee, J. Y., Tsolis, R. M. & Baumler, A. J. The microbiome and gut homeostasis. Science 377, eabp9960 (2022).
Cook, M. A. & Wright, G. D. The past, present, and future of antibiotics. Sci. Transl. Med. 14, eabo7793 (2022).
Smith, P. A. et al. Optimized arylomycins are a new class of Gram-negative antibiotics. Nature 561, 189–194 (2018).
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