Multiplexed screen identifies a Pseudomonas aeruginosa-specific small molecule targeting the outer membrane protein OprH and its interaction with LPS
Warrier, T.; Poulsen, B. E.; Barkho, S.; Bagnall, J.; Romano, K. P.; White, T.; Yu, X.; Kawate, T.; Nguyen, P. H.; Raines, K.; Ferrara, K.; Golas, A.; Fitzgerald, M.; Boeszoermenyi, A.; Kaushik, V.; Serrano-Wu, M.; Shoresh, N.; Hung, D. T.
Show abstract
SUMMARYThe surge of antimicrobial resistance threatens efficacy of current antibiotics, particularly against Pseudomonas aeruginosa, a highly resistant gram-negative pathogen. The asymmetric outer membrane (OM) of P. aeruginosa combined with its array of efflux pumps provide a barrier to xenobiotic accumulation, thus making antibiotic discovery challenging. We adapted PROSPECT1, a target-based, whole-cell screening strategy, to discover small molecule probes that kill P. aeruginosa mutants depleted for essential proteins localized at the OM. We identified BRD1401, a small molecule that has specific activity against a P. aeruginosa mutant depleted for the essential lipoprotein, OprL. Genetic and chemical biological studies identified that BRD1401 acts by targeting the OM {beta}-barrel protein OprH to disrupt its interaction with LPS and increase membrane fluidity. Studies with BRD1401 also revealed an interaction between OprL and OprH, directly linking the OM with peptidoglycan. Thus, a whole-cell, multiplexed screen can identify species-specific chemical probes to reveal novel pathogen biology.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Chemically-induced targeted protein degradation in mycobacteria uncovers antibacterial effects and potentiates antibiotic efficacy 96%
- Antibiotic hypersensitivity signatures identify targets for attack in the Acinetobacter baumannii cell envelope 96%
- Escape mutations circumvent a tradeoff between resistance to beta-lactams and a beta-lactamase inhibitor 96%
Similar papers in this journal
- Antibiotic-induced accumulation of lipid II sensitizes bacteria to antimicrobial fatty acids 96%
- A covariation analysis reveals elements of selectivity in quorum sensing systems 96%
- Amoxicillin-resistant Streptococcus pneumoniae can be resensitized by targeting the mevalonate pathway as indicated by sCRilecs-seq 96%
Similar papers in this journal
- The mycomembrane differentially and heterogeneously restricts antibiotic permeation 96%
- A multiplexed, target-based phenotypic screening platform using CRISPR interference in Mycobacterium abscessus 96%
- An engineered prodrug selectively suppresses β-lactam resistant bacteria in a mixed microbial setting 95%
Similar papers in this journal
- An Inducible CRISPRi system for phenotypic analysis of essential genes in Pseudomonas aeruginosa 96%
- A bacterial inflammation sensor regulates c-di-GMP signaling, adhesion, and biofilm formation. 95%
- Understanding the biosynthesis, metabolic regulation, and anti-phytopathogen activity of 3,7-dihydroxytropolone in Pseudomonas spp. 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.