Computer-aided drug design to generate a unique antibiotic family.
Anti-Bacterial Agents
/ pharmacology
Drug Design
Animals
Computer-Aided Design
Microbial Sensitivity Tests
Humans
Drug Resistance, Multiple, Bacterial
/ drug effects
Colistin
/ pharmacology
Mice
Diabetic Foot
/ drug therapy
Gram-Positive Bacteria
/ drug effects
Gram-Negative Bacteria
/ drug effects
Drug Synergism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
27 Sep 2024
27 Sep 2024
Historique:
received:
13
07
2022
accepted:
23
09
2024
medline:
28
9
2024
pubmed:
28
9
2024
entrez:
27
9
2024
Statut:
epublish
Résumé
The World Health Organization has identified antibiotic resistance as one of the three greatest threats to human health. The need for antibiotics is a pressing matter that requires immediate attention. Here, computer-aided drug design is used to develop a structurally unique antibiotic family targeting holo-acyl carrier protein synthase (AcpS). AcpS is a highly conserved enzyme essential for bacterial survival that catalyzes the first step in lipid synthesis. To the best of our knowledge, there are no current antibiotics targeting AcpS making this drug development program of high interest. We synthesize a library of > 700 novel compounds targeting AcpS, from which 33 inhibit bacterial growth in vitro at ≤ 2 μg/mL. We demonstrate that compounds from this class have stand-alone activity against a broad spectrum of Gram-positive organisms and synergize with colistin to enable coverage of Gram-negative species. We demonstrate efficacy against clinically relevant multi-drug resistant strains in vitro and in animal models of infection in vivo including a difficult-to-treat ischemic infection exemplified by diabetic foot ulcer infections in humans. This antibiotic family could form the basis for several multi-drug-resistant antimicrobial programs.
Identifiants
pubmed: 39333560
doi: 10.1038/s41467-024-52797-2
pii: 10.1038/s41467-024-52797-2
doi:
Substances chimiques
Anti-Bacterial Agents
0
Colistin
Z67X93HJG1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8317Subventions
Organisme : Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)
ID : SOP-159230
Informations de copyright
© 2024. The Author(s).
Références
Balasegaram, M. & Piddock, L. J. V. The Global Antibiotic Research and Development Partnership (GARDP) not-for-profit model of antibiotic development. ACS Infect. Dis. 6, 1295–1298 (2020).
pubmed: 32406675
doi: 10.1021/acsinfecdis.0c00101
Antimicrobial Resistance, C. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 399, 629–655 (2022).
doi: 10.1016/S0140-6736(21)02724-0
De Oliveira, D. M. P. et al. Antimicrobial Resistance in ESKAPE Pathogens. Clin. Microbiol. Rev. 33 https://doi.org/10.1128/CMR.00181-19 (2020).
Kuehn, B. Evolution of “Nightmare Bacteria”. JAMA 319, 2070 (2018).
pubmed: 29800188
Pendleton, J. N., Gorman, S. P. & Gilmore, B. F. Clinical relevance of the ESKAPE pathogens. Expert Rev. Anti Infect. Ther. 11, 297–308 (2013).
pubmed: 23458769
doi: 10.1586/eri.13.12
Roemer, T., Davies, J., Giaever, G. & Nislow, C. Bugs, drugs and chemical genomics. Nat. Chem. Biol. 8, 46–56 (2011).
pubmed: 22173359
doi: 10.1038/nchembio.744
Darby, E. M. et al. Molecular mechanisms of antibiotic resistance revisited. Nat. Rev. Microbiol. 21, 280–295 (2023).
pubmed: 36411397
doi: 10.1038/s41579-022-00820-y
Walesch, S. et al. Fighting antibiotic resistance-strategies and (pre)clinical developments to find new antibacterials. EMBO Rep. 24, e56033 (2023).
pubmed: 36533629
doi: 10.15252/embr.202256033
Cook, M. A. & Wright, G. D. The past, present, and future of antibiotics. Sci. Transl. Med. 14, eabo7793 (2022).
pubmed: 35947678
doi: 10.1126/scitranslmed.abo7793
Durand-Reville, T. F. et al. Rational design of a new antibiotic class for drug-resistant infections. Nature 597, 698–702 (2021).
pubmed: 34526714
doi: 10.1038/s41586-021-03899-0
Li, Q. et al. Synthetic group A streptogramin antibiotics that overcome Vat resistance. Nature 586, 145–150 (2020).
pubmed: 32968273
pmcid: 7546582
doi: 10.1038/s41586-020-2761-3
Smith, P. A. et al. Optimized arylomycins are a new class of Gram-negative antibiotics. Nature 561, 189–194 (2018).
pubmed: 30209367
doi: 10.1038/s41586-018-0483-6
Ling, L. L. et al. A new antibiotic kills pathogens without detectable resistance. Nature 517, 455–459 (2015).
pubmed: 25561178
pmcid: 7414797
doi: 10.1038/nature14098
Seiple, I. B. et al. A platform for the discovery of new macrolide antibiotics. Nature 533, 338–345 (2016).
pubmed: 27193679
pmcid: 6526944
doi: 10.1038/nature17967
Luther, A. et al. Chimeric peptidomimetic antibiotics against Gram-negative bacteria. Nature 576, 452–458 (2019).
pubmed: 31645764
doi: 10.1038/s41586-019-1665-6
Culp, E. J. et al. Evolution-guided discovery of antibiotics that inhibit peptidoglycan remodelling. Nature 578, 582–587 (2020).
pubmed: 32051588
doi: 10.1038/s41586-020-1990-9
Lehar, S. M. et al. Novel antibody-antibiotic conjugate eliminates intracellular S. aureus. Nature 527, 323–328 (2015).
pubmed: 26536114
doi: 10.1038/nature16057
Haydon, D. J. et al. An inhibitor of FtsZ with potent and selective anti-staphylococcal activity. Science 321, 1673–1675 (2008).
pubmed: 18801997
doi: 10.1126/science.1159961
Kumar, M. et al. Novel FtsZ inhibitor with potent activity against Staphylococcus aureus. J. Antimicrob. Chemother. 76, 2867–2874 (2021).
pubmed: 34383913
doi: 10.1093/jac/dkab270
Hamamoto, H. et al. Lysocin E is a new antibiotic that targets menaquinone in the bacterial membrane. Nat. Chem. Biol. 11, 127–133 (2015).
pubmed: 25485686
doi: 10.1038/nchembio.1710
Barbieri, R. et al. Yersinia pestis: the natural history of plague. Clin. Microbiol. Rev. 34 https://doi.org/10.1128/CMR.00044-19 (2020).
Piret, J. & Boivin, G. Pandemics throughout history. Front. Microbiol. 11, 631736 (2020).
pubmed: 33584597
doi: 10.3389/fmicb.2020.631736
Pahil, K. S. et al. A new antibiotic traps lipopolysaccharide in its intermembrane transporter. Nature 625, 572–577 (2024).
pubmed: 38172635
pmcid: 10794137
doi: 10.1038/s41586-023-06799-7
Wang, Z. et al. A naturally inspired antibiotic to target multidrug-resistant pathogens. Nature 601, 606–611 (2022).
pubmed: 34987225
pmcid: 10321319
doi: 10.1038/s41586-021-04264-x
Wong, F. et al. Discovery of a structural class of antibiotics with explainable deep learning. Nature 626, 177–185 (2024).
pubmed: 38123686
doi: 10.1038/s41586-023-06887-8
Zampaloni, C. et al. A novel antibiotic class targeting the lipopolysaccharide transporter. Nature 625, 566–571 (2024).
pubmed: 38172634
pmcid: 10794144
doi: 10.1038/s41586-023-06873-0
Matilde Monteiro-Sores, J. V. S. IDF atlas reports: diabetes foot-related complications. 1–23 (2022).
Armstrong, D. G. et al. Five year mortality and direct costs of care for people with diabetic foot complications are comparable to cancer. J. Foot Ankle Res. 13, 16 (2020).
pubmed: 32209136
pmcid: 7092527
doi: 10.1186/s13047-020-00383-2
Armstrong, D. G., Tan, T. W., Boulton, A. J. M. & Bus, S. A. Diabetic foot ulcers: a review. JAMA 330, 62–75 (2023).
pubmed: 37395769
pmcid: 10723802
doi: 10.1001/jama.2023.10578
Chirgadze, N. Y., Briggs, S. L., McAllister, K. A., Fischl, A. S. & Zhao, G. Crystal structure of Streptococcus pneumoniae acyl carrier protein synthase: an essential enzyme in bacterial fatty acid biosynthesis. EMBO J. 19, 5281–5287 (2000).
pubmed: 11032795
pmcid: 314021
doi: 10.1093/emboj/19.20.5281
Keating, M. M., Gong, H. & Byers, D. M. Identification of a key residue in the conformational stability of acyl carrier protein. Biochim. Biophys. Acta 1601, 208–214 (2002).
pubmed: 12445484
doi: 10.1016/S1570-9639(02)00470-3
Nguyen, C. et al. Trapping the dynamic acyl carrier protein in fatty acid biosynthesis. Nature 505, 427–431 (2014).
pubmed: 24362570
doi: 10.1038/nature12810
Parris, K. D. et al. Crystal structures of substrate binding to Bacillus subtilis holo-(acyl carrier protein) synthase reveal a novel trimeric arrangement of molecules resulting in three active sites. Structure 8, 883–895 (2000).
pubmed: 10997907
doi: 10.1016/S0969-2126(00)00178-7
Jerga, A. & Rock, C. O. Acyl-Acyl carrier protein regulates transcription of fatty acid biosynthetic genes via the FabT repressor in Streptococcus pneumoniae. J. Biol. Chem. 284, 15364–15368 (2009).
pubmed: 19376778
pmcid: 2708833
doi: 10.1074/jbc.C109.002410
Wong, H. C., Liu, G., Zhang, Y. M., Rock, C. O. & Zheng, J. The solution structure of acyl carrier protein from Mycobacterium tuberculosis. J. Biol. Chem. 277, 15874–15880 (2002).
pubmed: 11825906
doi: 10.1074/jbc.M112300200
McAllister, K. A., Peery, R. B. & Zhao, G. Acyl carrier protein synthases from gram-negative, gram-positive, and atypical bacterial species: Biochemical and structural properties and physiological implications. J. Bacteriol. 188, 4737–4748 (2006).
pubmed: 16788183
pmcid: 1483016
doi: 10.1128/JB.01917-05
Gong, H., Murphy, A., McMaster, C. R. & Byers, D. M. Neutralization of acidic residues in helix II stabilizes the folded conformation of acyl carrier protein and variably alters its function with different enzymes. J. Biol. Chem. 282, 4494–4503 (2007).
pubmed: 17179150
doi: 10.1074/jbc.M608234200
Flugel, R. S., Hwangbo, Y., Lambalot, R. H., Cronan, J. E. Jr. & Walsh, C. T. Holo-(acyl carrier protein) synthase and phosphopantetheinyl transfer in Escherichia coli. J. Biol. Chem. 275, 959–968 (2000).
pubmed: 10625633
doi: 10.1074/jbc.275.2.959
Marcella, A. M., Culbertson, S. J., Shogren-Knaak, M. A. & Barb, A. W. Structure, high affinity, and negative cooperativity of the Escherichia coli Holo-(acyl carrier protein):Holo-(acyl carrier protein) synthase complex. J. Mol. Biol. 429, 3763–3775 (2017).
pubmed: 29054754
doi: 10.1016/j.jmb.2017.10.015
Flynn, K., Mahmoud, N. N., Sharifi, S., Gould, L. J. & Mahmoudi, M. Chronic wound healing models. ACS Pharm. Transl. Sci. 6, 783–801 (2023).
doi: 10.1021/acsptsci.3c00030
Tan, M. L. L., Chin, J. S., Madden, L. & Becker, D. L. Challenges faced in developing an ideal chronic wound model. Expert Opin. Drug Discov. 18, 99–114 (2023).
pubmed: 36573018
doi: 10.1080/17460441.2023.2158809
Chien, S. & Wilhelmi, B. J. A simplified technique for producing an ischemic wound model. J. Vis. Exp. e3341 https://doi.org/10.3791/3341 (2012).
Lovasova, V. et al. Animal experimental models of ischemic wounds—a review of literature. Wound Repair Regen. 30, 268–281 (2022).
pubmed: 35138685
doi: 10.1111/wrr.12996
Senneville, E. et al. IWGDF/IDSA guidelines on the diagnosis and treatment of diabetes-related foot infections (IWGDF/IDSA 2023). Diabetes Metab. Res. Rev. 40, e3687 (2024).
pubmed: 37779323
doi: 10.1002/dmrr.3687
Lipsky, B. A. & Hoey, C. Topical antimicrobial therapy for treating chronic wounds. Clin. Infect. Dis. 49, 1541–1549 (2009).
pubmed: 19842981
doi: 10.1086/644732
Dowhan, W., Vitrac, H. & Bogdanov, M. Lipid-assisted membrane protein folding and topogenesis. Protein J. 38, 274–288 (2019).
pubmed: 30937648
pmcid: 6589379
doi: 10.1007/s10930-019-09826-7
Li, Y. et al. LPS remodeling is an evolved survival strategy for bacteria. Proc. Natl Acad. Sci. USA 109, 8716–8721 (2012).
pubmed: 22586119
pmcid: 3365160
doi: 10.1073/pnas.1202908109
Zeng, D. et al. Mutants resistant to LpxC inhibitors by rebalancing cellular homeostasis. J. Biol. Chem. 288, 5475–5486 (2013).
pubmed: 23316051
pmcid: 3581379
doi: 10.1074/jbc.M112.447607
Coggins, B. E. et al. Structure of the LpxC deacetylase with a bound substrate-analog inhibitor. Nat. Struct. Biol. 10, 645–651 (2003).
pubmed: 12833153
pmcid: 6783277
doi: 10.1038/nsb948
Jackman, J. E., Raetz, C. R. & Fierke, C. A. Site-directed mutagenesis of the bacterial metalloamidase UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC). Identification of the zinc binding site. Biochemistry 40, 514–523 (2001).
pubmed: 11148046
doi: 10.1021/bi001872g
Surivet, J. P. et al. Discovery of novel inhibitors of LpxC displaying potent in vitro activity against Gram-negative bacteria. J. Med. Chem. 63, 66–87 (2020).
pubmed: 31804826
doi: 10.1021/acs.jmedchem.9b01604
Garcia-Quintanilla, M. et al. Inhibition of LpxC increases antibiotic susceptibility in Acinetobacter baumannii. Antimicrob. Agents Chemother. 60, 5076–5079 (2016).
pubmed: 27270288
pmcid: 4958213
doi: 10.1128/AAC.00407-16
Phee, L. M., Betts, J. W., Bharathan, B. & Wareham, D. W. Colistin and fusidic acid, a novel potent synergistic combination for treatment of multidrug-resistant Acinetobacter baumannii infections. Antimicrob. Agents Chemother. 59, 4544–4550 (2015).
pubmed: 25987639
pmcid: 4505221
doi: 10.1128/AAC.00753-15
Cirioni, O. et al. Enhanced efficacy of combinations of Pexiganan with colistin versus Acinetobacter baumannii in experimental sepsis. Shock 46, 219–225 (2016).
pubmed: 26849630
doi: 10.1097/SHK.0000000000000584
Bergen, P. J. et al. Optimizing polymyxin combinations against resistant Gram-negative bacteria. Infect. Dis. Ther. 4, 391–415 (2015).
pubmed: 26645096
pmcid: 4675771
doi: 10.1007/s40121-015-0093-7
Petrosillo, N., Ioannidou, E. & Falagas, M. E. Colistin monotherapy vs. combination therapy: evidence from microbiological, animal and clinical studies. Clin. Microbiol. Infect. 14, 816–827 (2008).
pubmed: 18844682
doi: 10.1111/j.1469-0691.2008.02061.x
Lakhe, M., Patil, S. V., Korukonda, K. & Bhargava, A. Polymyxin-B combination therapy—a dire need to safeguard our last hope. J. Glob. Infect. Dis. 8, 125–126 (2016).
pubmed: 27621565
pmcid: 4997798
doi: 10.4103/0974-777X.188599
Chung, J. H., Bhat, A., Kim, C. J., Yong, D. & Ryu, C. M. Combination therapy with polymyxin B and netropsin against clinical isolates of multidrug-resistant Acinetobacter baumannii. Sci. Rep. 6, 28168 (2016).
pubmed: 27306928
pmcid: 4910107
doi: 10.1038/srep28168
Stein, C. et al. Three dimensional checkerboard synergy analysis of colistin, meropenem, tigecycline against multidrug-resistant clinical Klebsiella pneumonia isolates. PLoS One 10, e0126479 (2015).
pubmed: 26067824
pmcid: 4465894
doi: 10.1371/journal.pone.0126479
Malachowa, N., Kobayashi, S. D., Braughton, K. R. & DeLeo, F. R. Mouse model of Staphylococcus aureus skin infection. Methods Mol. Biol. 1031, 109–116 (2013).
pubmed: 23824894
doi: 10.1007/978-1-62703-481-4_14
Sisco, M. & Mustoe, T. A. Animal models of ischemic wound healing. Toward an approximation of human chronic cutaneous ulcers in rabbit and rat. Methods Mol. Med. 78, 55–65 (2003).
pubmed: 12825261
Volk, S. W., Radu, A., Zhang, L. & Liechty, K. W. Stromal progenitor cell therapy corrects the wound-healing defect in the ischemic rabbit ear model of chronic wound repair. Wound Repair Regen. 15, 736–747 (2007).
pubmed: 17971020
doi: 10.1111/j.1524-475X.2007.00277.x
Xie, P. et al. Topical administration of oxygenated hemoglobin improved wound healing in an ischemic rabbit ear model. Plast. Reconstr. Surg. 137, 534–543 (2016).
pubmed: 26818288
doi: 10.1097/01.prs.0000475763.94203.52