ArticleNature communications2023
Efflux pump gene amplifications bypass necessity of multiple target mutations for resistance against dual-targeting antibiotic.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- Genomic and Phenotypic Classification of Staphylococcus Species Isolated From Delhi Air.Environmental microbiology reports · 2026Article
- Modulation of rob expression accelerates development of antibiotic resistance in Yersinia enterocolitica.Nucleic acids research · 2026Article
- Resistance potentiators: Evolutionary catalysts of antibiotic resistance.PLoS biology · 2026Article
- Improved Cas9-targeted nanopore sequencing facilitates ultra-deep analysis of genomic variation.Cell reports methods · 2026Article
- Genome-wide characteristics, antibiotic resistance, and pathogenicity analysis of Streptococcus parasuis strains isolated from diseased pigs.BMC microbiology · 2026Article
- Dipiperazine-Phenyl Derivatives Based on Convergent Molecular Platforms Can Reverse Multidrug Resistance in Gram-Negative Bacteria by Inhibiting Efflux and Permeabilizing Cell Membranes.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- NIR enhanced nanozyme and synergy with ineffective antibiotic activities of BSA-AgPhotochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology · 2026Article
- Transient AdeABC-mediated eravacycline resistance in carbapenem-resistant Acinetobacter baumannii ST2: a mutation-independent efflux pump adaptation.Annals of clinical microbiology and antimicrobials · 2026Article
- Extended-Spectrum Beta-Lactamase (ESBL)-Producing E. coli in Livestock and Free-Roaming Wildlife: A Combined Phenotyping-Whole-Genome Sequencing One Health Approach.Transboundary and emerging diseases · 2026Article
- Modulators of gene amplification alter evolution of antibiotic resistance in Staphylococcus aureus.PLoS genetics · 2025Article
- Molecular characterization of fluoroquinolone resistance in invasive clinical isolates of Streptococcus pneumoniae susceptible to delafloxacin.The Journal of antimicrobial chemotherapy · 2025Article
- Repurposing Drug Metabolites into Dual β-Adrenergic Receptor-Carbonic Anhydrase Modulators as Potential Tools for Ocular Disorders.Journal of medicinal chemistry · 2025Article
- Driving factors for beta-lactam resistance gene amplification duringAntimicrobial agents and chemotherapy · 2025Article
- Collateral sensitivity and cross-resistance in six species of bacteria exposed to six classes of antibiotics.Microbiology spectrum · 2025Article
- Methicillin-ResistantAntibiotics (Basel, Switzerland) · 2025Review
- Investigation of potential relationship betweenmazEF3, relJK, and vapBC3 genes and antimicrobial resistance inMycobacterium bovis.BMC infectious diseases · 2025Article
- Transcriptomic and proteomic ramifications of segmental amplification inProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Heteroresistance in Enterobacter cloacae complex caused by variation in transient gene amplification events.npj antimicrobials and resistance · 2025Article
- Exploring the principles behind antibiotics with limited resistance.Nature communications · 2025Article
- Comprehensive Genome Analysis of a Human-Derived β-Lactam-ResistantInfection and drug resistance · 2025Article
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Authors and funding
3 authors.
Funding
Abstract
Antibiotics that have multiple cellular targets theoretically reduce the frequency of resistance evolution, but adaptive trajectories and resistance mechanisms against such antibiotics are understudied. Here we investigate these in methicillin resistant Staphylococcus aureus (MRSA) using experimental evolution upon exposure to delafloxacin (DLX), a novel fluoroquinolone that targets both DNA gyrase and topoisomerase IV. We show that selection for coding sequence mutations and genomic amplifications of the gene encoding a poorly characterized efflux pump, SdrM, leads to high DLX resistance, circumventing the requirement for mutations in both target enzymes. In the evolved populations, sdrM overexpression due to genomic amplifications containing sdrM and two adjacent genes encoding efflux pumps results in high DLX resistance, while the adjacent hitchhiking efflux pumps contribute to streptomycin cross-resistance. Further, lack of sdrM necessitates mutations in both target enzymes to evolve DLX resistance, and sdrM thus increases the frequency of resistance evolution. Finally, sdrM mutations and amplifications are similarly selected in two diverse clinical isolates, indicating the generality of this DLX resistance mechanism. Our study highlights that instead of reduced rates of resistance, evolution of resistance to multi-targeting antibiotics can involve alternate high-frequency evolutionary paths, that may cause unexpected alterations of the fitness landscape, including antibiotic cross-resistance.
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