ArticleAntimicrobial agents and chemotherapy2012
The antibiotic resistance arrow of time: efflux pump induction is a general first step in the evolution of mycobacterial drug resistance.
Article in Antimicrobial agents and chemotherapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 109 papers, 1 of them a synthesis that pooled it.
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Who cites it
109 citing papers in PubMed, 1 synthesis or guideline pooled it, 191 citations in OpenAlex.
- Systematic and quantitative analyses of hollow fiber model ofMicrobiology spectrum · 2026Pooled it
- The pyrazinamide susceptibility breakpoint above which combination therapy fails.The Journal of antimicrobial chemotherapy · 2014Trial
- Macrolide-resistantJournal of clinical tuberculosis and other mycobacterial diseases · 2026Review
- Designing Antibiotics with Inherent Resistance to Efflux as a Strategy to Revive Discovery against Multidrug-Resistant Pathogens.Journal of medicinal chemistry · 2026Article
- Sulbactam-durlobactam plus ceftriaxone dosing and novel treatment regimens forAntimicrobial agents and chemotherapy · 2026Article
- Novel regimens for treatment ofbioRxiv : the preprint server for biology · 2026Article
- Rifamycin-, macrolide-, and ethambutol-free combinations to treatThe international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease · 2026Article
- The Role of β-Lactam Antibiotics in Treating Mycobacterium abscessus: From Laboratory Insights to Clinical Applications and the Case for Clinical Trials.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2026Review
- Preclinical pharmacokinetics/pharmacodynamics studies defining the role of ethambutol inAntimicrobial agents and chemotherapy · 2026Article
- Preclinical evaluation of epetraborole in the hollow fibre system model of Mycobacterium abscessus lung disease.The Journal of antimicrobial chemotherapy · 2026Article
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- Challenges in the Diagnosis and Treatment of Mycobacterium abscessus Infections.Revista da Sociedade Brasileira de Medicina Tropical · 2026Review
- Antibiotic resistance inFrontiers in microbiology · 2026Review
- Pharmacodynamic evidence for tedizolid use inIJTLD open · 2026Article
- Epetraborole pharmacokinetics/pharmacodynamics in the hollow fiber system model ofAntimicrobial agents and chemotherapy · 2025Article
- Article
- Sulbactam-Durlobactam Plus Ceftriaxone Dosing and Novel Treatment Regimens forbioRxiv : the preprint server for biology · 2025Article
- Antimicrobial resistance mechanisms in non-tuberculous mycobacteria.Folia microbiologica · 2025Review
- Tigecycline pharmacodynamics in the hollow fiber system ofbioRxiv : the preprint server for biology · 2025Article
- Imipenem Pharmacokinetics/Pharmacodynamics in Preclinical Hollow Fiber Model, Dose Finding in Virtual Patients, and Clinical Evidence of Efficacy for Mycobacterium abscessus Lung Disease.The Journal of infectious diseases · 2025Article
49 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
We hypothesize that low-level efflux pump expression is the first step in the development of high-level drug resistance in mycobacteria. We performed 28-day azithromycin dose-effect and dose-scheduling studies in our hollow-fiber model of disseminated Mycobacterium avium-M. intracellulare complex. Both microbial kill and resistance emergence were most closely linked to the within-macrophage area under the concentration-time curve (AUC)/MIC ratio. Quantitative PCR revealed that subtherapeutic azithromycin exposures over 3 days led to a 56-fold increase in expression of MAV_3306, which encodes a putative ABC transporter, and MAV_1406, which encodes a putative major facilitator superfamily pump, in M. avium. By day 7, a subpopulation of M. avium with low-level resistance was encountered and exhibited the classic inverted U curve versus AUC/MIC ratios. The resistance was abolished by an efflux pump inhibitor. While the maximal microbial kill started to decrease after day 7, a population with high-level azithromycin resistance appeared at day 28. This resistance could not be reversed by efflux pump inhibitors. Orthologs of pumps encoded by MAV_3306 and MAV_1406 were identified in Mycobacterium tuberculosis, Mycobacterium leprae, Mycobacterium marinum, Mycobacterium abscessus, and Mycobacterium ulcerans. All had highly conserved protein secondary structures. We propose that induction of several efflux pumps is the first step in a general pathway to drug resistance that eventually leads to high-level chromosomal-mutation-related resistance in mycobacteria as ordered events in an "antibiotic resistance arrow of time."
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.