A Gram-negative-selective antibiotic that spares the gut microbiome

  • Maier, L. et al. Unravelling the collateral damage of antibiotics on gut bacteria. Nature 599, 120–124 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lynch, S. V. & Pedersen, O. The human intestinal microbiome in health and disease. New Eng. J. Med. 375, 2369–2379 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Schubert, A. M., Sinani, H. & Schloss, P. D. Antibiotic-induced alterations of the murine gut microbiota and subsequent effects on colonization resistance against Clostridium difficile. mBio 6, e00974 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Owens, R. C. Jr., Donskey, C. J., Gaynes, R. P., Loo, V. G. & Muto, C. A. Antimicrobial-associated risk factors for Clostridium difficile infection. Clin. Infect. Dis. 46, S19–S31 (2008).

    Article 
    PubMed 

    Google Scholar
     

  • Iizumi, T., Battaglia, T., Ruiz, V. & Perez Perez, G. I. Gut microbiome and antibiotics. Arch. Med. Res. 48, 727–734 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Poon, S. S. B. et al. Neonatal antibiotics have long term sex-dependent effects on the enteric nervous system. J. Phys. 600, 4303–4323 (2022).

    CAS 

    Google Scholar
     

  • Lange, K., Buerger, M., Stallmach, A. & Bruns, T. Effects of antibiotics on gut microbiota. Digest. Dis. 34, 260–268 (2016).

    Article 

    Google Scholar
     

  • Gu, S. et al. Effect of the short-term use of fluoroquinolone and β-lactam antibiotics on mouse gut microbiota. Infect. Drug Resist. 13, 4547–4558 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lofmark, S., Jernberg, C., Jansson, J. K. & Edlund, C. Clindamycin-induced enrichment and long-term persistence of resistant Bacteroides spp. and resistance genes. J. Antimicrob. Chemother. 58, 1160–1167 (2006).

    Article 
    PubMed 

    Google Scholar
     

  • Hertz, F. B. et al. Effects of antibiotics on the intestinal microbiota of mice. Antibiotics 9, 191 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lagier, J. C., Million, M., Hugon, P., Armougom, F. & Raoult, D. Human gut microbiota: repertoire and variations. Front. Cell Infect. Microbiol. 2, 136 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Singh, H. Management with colistin. Ind. J. Crit. Care. Med. 14, 161–162 (2010).

    Article 

    Google Scholar
     

  • Falagas, M. E. & Kasiakou, S. K. Colistin: the revival of polymyxins for the management of multidrug-resistant Gram-negative bacterial infections. Clin. Infect. Dis. 40, 1333–1341 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chatzidimitriou, M. et al. mcr genes conferring colistin resistance in Enterobacterales; a five year overview. Acta Med. Acad. 50, 365–371 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Rice, L. B. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J. Infect. Dis. 197, 1079–1081 (2008).

    Article 
    PubMed 

    Google Scholar
     

  • Hoffman, P. S. Antibacterial discovery: 21st century challenges. Antibiotics 9, 213–213 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nickerson, N. N. et al. A novel inhibitor of the LolCDE ABC transporter essential for lipoprotein trafficking in Gram-negative bacteria. Antimicrob. Agents Chemother. 62, e02151–02117 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, G. et al. Cell-based screen for discovering lipopolysaccharide biogenesis inhibitors. Proc. Natl Acad. Sci. USA 115, 6834–6839 (2018).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lehman, K. M. & Grabowicz, M. Countering Gram-negative antibiotic resistance: recent progress in disrupting the outer membrane with novel therapeutics. Antibiotics 8, 163 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Brown, M. F. et al. Potent inhibitors of LpxC for the treatment of Gram-negative infections. J. Med. Chem. 55, 914–923 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Miller, R. D. et al. A novel antibiotic targeting BamA identified by a computational search. Nat. Microbiol. 7, 1661–1672 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Imai, Y. et al. A new antibiotic selectively kills Gram-negative pathogens. Nature 576, 459–464 (2019).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Smith, P. A. et al. Optimized arylomycins are a new class of Gram-negative antibiotics. Nature 561, 189–194 (2018).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Tokuda, H. & Matsuyama, S.-I. Sorting of lipoproteins to the outer membrane in E. coli. Biochim. Biophys. Acta 1693, 5–13 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pathania, R. et al. Chemical genomics in Escherichia coli identifies an inhibitor of bacterial lipoprotein targeting. Nat. Chem. Biol. 5, 849–856 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Barker, C. A. et al. Degradation of MAC13243 and studies of the interaction of resulting thiourea compounds with the lipoprotein targeting chaperone LolA. Bioorg. Med. Chem. Lett. 23, 2426–2431 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hoang, H. H. et al. Outer membrane targeting of Pseudomonas aeruginosa proteins shows variable dependence on the components of Bam and Lol machineries. mBio 2, e00246–00211 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ito, H. et al. A new screening method to identify inhibitors of the Lol (localization of lipoproteins) system, a novel antibacterial target. Microbiol. Immun. 51, 263–270 (2007).

    Article 
    CAS 

    Google Scholar
     

  • Nayar, A. S. et al. Novel antibacterial targets and compounds revealed by a high-throughput cell wall reporter assay. J. Bacteriol. 197, 1726–1734 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, J. et al. Natural inhibitors targeting the localization of lipoprotein system in Vibrio parahaemolyticus. Int. J. Mol. Sci. 23, 14352 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Breidenstein, E. B. M. et al. SMT-738: a novel small-molecule inhibitor of bacterial lipoprotein transport targeting Enterobacteriaceae. Antimicrob. Agents Chemother. 68, e0069523 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Grabowicz, M. & Silhavy, T. J. Redefining the essential trafficking pathway for outer membrane lipoproteins. Proc. Natl Acad. Sci. USA 114, 4769–4774 (2017).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Richter, M. F. et al. Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature 545, 299–304 (2017).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Richter, M. F. & Hergenrother, P. J. The challenge of converting Gram-positive-only compounds into broad-spectrum antibiotics. Ann. NY Acad. Sci. 1435, 18–38 (2019).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Munoz, K. A. & Hergenrother, P. J. Facilitating compound entry as a means to discover antibiotics for Gram-negative bacteria. Acc. Chem. Res. 54, 1322–1333 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Prochnow, H. et al. Subcellular quantification of uptake in Gram-negative bacteria. Anal. Chem. 91, 1863–1872 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wexler, H. M. Bacteroides: the good, the bad, and the nitty-gritty. Clin. Microbiol. Rev. 20, 593–621 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nonejuie, P., Burkart, M., Pogliano, K. & Pogliano, J. Bacterial cytological profiling rapidly identifies the cellular pathways targeted by antibacterial molecules. Proc. Natl Acad. Sci. USA 110, 16169–16174 (2013).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Grabowicz, M. Lipoproteins and their trafficking to the outer membrane. EcoSal Plus 8, https://doi.org/10.1128/ecosalplus.ESP-0038-2018 (2019).

  • Tang, X. et al. Structural basis for bacterial lipoprotein relocation by the transporter LolCDE. Nat. Struct. Mol. Biol. 28, 347–355 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sharma, S. et al. Mechanism of LolCDE as a molecular extruder of bacterial triacylated lipoproteins. Nat. Commun. 12, 4687 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Buffie, C. G. et al. Profound alterations of intestinal microbiota following a single dose of clindamycin results in sustained susceptibility to Clostridium difficile-induced colitis. Infect. Immun. 80, 62–73 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lesniak, N. A., Schubert, A. M., Sinani, H. & Schloss, P. D. Clearance of Clostridioides difficile colonization is associated with antibiotic-specific bacterial changes. mSphere 6, e01238-20 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Feuerstadt, P., Theriault, N. & Tillotson, G. The burden of CDI in the United States: a multifactorial challenge. BMC Infect. Dis. 23, 132 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Garcia Chavez, M. et al. Synthesis of fusidic acid derivatives yields a potent antibiotic with an improved resistance profile. ACS Infect. Dis. 7, 493–505 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Oefner, C. et al. Increased hydrophobic interactions of iclaprim with Staphylococcus aureus dihydrofolate reductase are responsible for the increase in affinity and antibacterial activity. J. Antimicrob. Chemother. 63, 687–698 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Purnapatre, K. P. et al. In vitro and in vivo activities of DS86760016, a novel leucyl-tRNA synthetase inhibitor for Gram-negative pathogens. Antimicrob. Agents Chemother. 62, e01987-17 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schuster, M. et al. Peptidomimetic antibiotics disrupt the lipopolysaccharide transport bridge of drug-resistant Enterobacteriaceae. Sci. Adv. 9, eadg3683 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rana, P. et al. FabI (enoyl acyl carrier protein reductase)—a potential broad spectrum therapeutic target and its inhibitors. Eur. J. Med. Chem. 208, 112757 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Parker, E. N. et al. An iterative approach guides discovery of the FabI inhibitor fabimycin, a late-stage antibiotic candidate with in vivo efficacy against drug-resistant Gram-negative infections. ACS Cent. Sci. 8, 1145–1158 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yao, J. et al. A pathogen-selective antibiotic minimizes disturbance to the microbiome. Antimicrob. Agents Chemother. 60, 4264–4273 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Konovalova, A., Kahne, D. E. & Silhavy, T. J. Outer membrane biogenesis. Annu. Rev. Microbiol. 71, 539–556 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ho, H. et al. Structural basis for dual-mode inhibition of the ABC transporter MsbA. Nature 557, 196–201 (2018).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Silver, L. L. A Gestalt approach to Gram-negative entry. Bioorg. Med. Chem. 24, 6379–6389 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pandit, K. R. & Klauda, J. B. Membrane models of E. coli containing cyclic moieties in the aliphatic lipid chain. Biochim. Biophys. Acta 1818, 1205–1210 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W. & Klein, M. L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79, 926–935 (1983).

    Article 
    ADS 
    CAS 

    Google Scholar
     

  • Jo, S., Kim, T., Iyer, V. G. & Im, W. CHARMM-GUI: a web-based graphical user interface for CHARMM. J. Comput. Chem. 29, 1859–1865 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Licari, G., Dehghani-Ghahnaviyeh, S. & Tajkhorshid, E. Membrane Mixer: a toolkit for efficient shuffling of lipids in heterogeneous biological membranes. J. Chem. Inform. Model. 62, 986–996 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Humphrey, W., Dalke, A. & Schulten, K. VMD: visual molecular dynamics. J. Mol. Graph. 14, 27–38 (1996). 33-38.

    Article 

    Google Scholar
     

  • Trott, O. & Olson, A. J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31, 455–461 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Phillips, J. C. et al. Scalable molecular dynamics on CPU and GPU architectures with NAMD. J. Chem. Phys. 153, 044130 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Phillips, J. C. et al. Scalable molecular dynamics with NAMD. J. Comput. Chem. 26, 1781–1802 (2005).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hart, K. et al. Optimization of the CHARMM additive force field for DNA: improved treatment of the BI/BII conformational equilibrium. J. Chem. Theor. Comput. 8, 348–362 (2012).

    Article 
    CAS 

    Google Scholar
     

  • Klauda, J. B. et al. Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. J. Phys. Chem. B 114, 7830–7843 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Darden, T., York, D. & Pedersen, L. Particle mesh Ewald: an N·log(N) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089–10092 (1993).

    Article 
    ADS 
    CAS 

    Google Scholar
     

  • Ryckaert, J. P., Ciccotti, G. & Berendsen, H. J. C. Numerical integration of the Cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J. Comput. Phys. 23, 327–341 (1977).

    Article 
    ADS 
    CAS 

    Google Scholar
     

  • Martyna, G. J., Tobias, D. J. & Klein, M. L. Constant-pressure molecular-dynamics algorithms. J. Chem. Phys. 101, 4177–4189 (1994).

    Article 
    ADS 
    CAS 

    Google Scholar
     

  • Feller, S. E., Zhang, Y. H., Pastor, R. W. & Brooks, B. R. Constant-pressure molecular-dynamics simulation—the Langevin piston method. J. Chem. Phys. 103, 4613–4621 (1995).

    Article 
    ADS 
    CAS 

    Google Scholar
     

  • Andrews, S. Fast QC: a quality control tool for high throughput sequence data. http://www.bioinformatics.babraham.ac.uk/projects/fastqc/ (2016).

  • Callahan, B. J. et al. DADA2: High-resolution sample inference from Illumina amplicon data. Nat. Method 13, 581–583 (2016).

    Article 
    CAS 

    Google Scholar
     

  • Lan, Y., Wang, Q., Cole, J. R. & Rosen, G. L. Using the RDP classifier to predict taxonomic novelty and reduce the search space for finding novel organisms. PLoS ONE 7, e32491 (2012).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Quast, C. et al. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res. 41, D590–D596 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • McLaren, M. R. Silva SSU taxonomic training data formatted for DADA2. Zenodo https://doi.org/10.5281/zenodo.3986799 (2020).

  • Wright, E. S. DECIPHER: harnessing local sequence context to improve protein multiple sequence alignment. BMC Bioinformatics 16, 322 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Price, M. N., Dehal, P. S. & Arkin, A. P. FastTree 2—approximately maximum-likelihood trees for large alignments. PLoS ONE 5, e9490 (2010).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • R: A Language and Environment for Statistical Computing, v. 4.2.1 (R Foundation for Statistical Computing, 2019).

  • McMurdie, P. J. & Holmes, S. phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PLoS ONE 8, e61217 (2013).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Oksanen, J. et al. vegan: Community ecology package. https://CRAN.R-project.org/package=vegan (2017).

  • Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Holmes, J. HPCBio/hergenrother-16S-mouse-2022Sept: Initial release. https://doi.org/10.5281/zenodo.10980656 (2024).

  • 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).

    Article 
    CAS 
    PubMed 

    Google Scholar
     


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