Large-scale combination screens reveal small-molecule sensitization of antibiotic-resistant gram-negative ESKAPE pathogens

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Author(s)
Tse, Megan
•
Zhu, Meilin
•
Peters, Benjamin
•
Hamami, Efrat
•
Chen, Julie
•
Davis, Kathleen
•
Nitz, Samuel
•
Weller, Juliane
•
Warrier, Thu
•
Hunt, Diana
Date Issued
March 24, 2025
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Citation
M.W. Tse, M. Zhu, B. Peters, E. Hamami, J. Chen, K.P. Davis, S. Nitz, J. Weller, T. Warrier, D.K. Hunt, Y. Morales, T. Kawate, J.L. Gaulin, J.H. Come, J. Hernandez-Bird, W. Huo, I. Neisewander, X. Yu, J.A. Aceves-Salvador, L.L. Kiessling, D.T. Hung, J. Mecsas, B.B. Aldridge, R.R. Isberg, & P.C. Blainey, Large-scale combination screens reveal small-molecule sensitization of antibiotic-resistant gram-negative ESKAPE pathogens, Proc. Natl. Acad. Sci. U.S.A. 122 (13) e2402017122 (2025).
Version
Final published version
Abstract
There is an unmet need for new antibiotic therapies effective against the multidrug-resistant, bacterial pathogens. Combination therapies have the potential to overcome resistance and broaden the spectrum of existing antibiotics. In this study, we use DropArray, a massively parallel combinatorial screening tool, to assay more than 1.3 million combinations of small molecules against the high-priority pathogens, Acinetobacter baumannii , Klebsiella pneumoniae , and Pseudomonas aeruginosa. We identified a synthetic small molecule potentiator, P2-56, of the antibiotic rifampin effective in A. baumannii and K. pneumoniae. We generated P2-56-3, a more potent derivative of P2-56, and found that it likely potentiates rifampin by compromising the outer membrane integrity. Our study demonstrates a highthroughput strategy for identifying antibiotic potentiators against multidrug-resistant bacteria.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Broad Institute of MIT and Harvard
Massachusetts Institute of Technology. Microbiology Graduate Program
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1073/pnas.2402017122
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