RNA Sequencing Elucidates Drug-Specific Mechanisms of Antibiotic Tolerance and Resistance in Mycobacterium abscessus
| Autor: | Wouter Hoefsloot, Huub J. M. Op den Camp, Jasper J N Sangen, Kornelia Neveling, Jordy P. M. Coolen, Michael Kwint, R. Andres Floto, Sophie Burbaud, Jodie A. Schildkraut, Heiman F. L. Wertheim, Jakko van Ingen, Lindsey H.M. te Brake |
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| Rok vydání: | 2022 |
| Předmět: |
nontuberculous mycobacteria
antibiotic resistance Multidrug tolerance medicine.drug_class Antibiotics Mycobacterium Infections Nontuberculous Microbial Sensitivity Tests Tigecycline Mycobacterium abscessus Microbiology Clofazimine Antibiotic resistance Mechanisms of Resistance Clarithromycin medicine Humans Pharmacology (medical) Pharmacology Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] biology Sequence Analysis RNA RNA sequencing bacterial infections and mycoses biology.organism_classification Anti-Bacterial Agents Kinetics lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] Infectious Diseases Amikacin Ecological Microbiology M. abscessus RNA medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy, 66, 1, pp. 1-24 Antimicrobial Agents and Chemotherapy, 66 Antimicrobial Agents and Chemotherapy, 66, 1-24 Antimicrobial Agents and Chemotherapy, 66, 1 Antimicrobial Agents and Chemotherapy |
| ISSN: | 0066-4804 |
| DOI: | 10.1128/aac.01509-21 |
| Popis: | Contains fulltext : 248649.pdf (Publisher’s version ) (Open Access) Mycobacterium abscessus is an opportunistic pathogen notorious for its resistance to most classes of antibiotics and low cure rates. M. abscessus carries an array of mostly unexplored defense mechanisms. A deeper understanding of antibiotic resistance and tolerance mechanisms is pivotal in development of targeted therapeutic regimens. We provide the first description of all major transcriptional mechanisms of tolerance to all antibiotics recommended in current guidelines, using RNA sequencing-guided experiments. M. abscessus ATCC 19977 bacteria were subjected to subinhibitory concentrations of clarithromycin (CLR), amikacin (AMK), tigecycline (TIG), cefoxitin (FOX), and clofazimine (CFZ) for 4 and 24 h, followed by RNA sequencing. To confirm key mechanisms of tolerance suggested by transcriptomic responses, we performed time-kill kinetic analysis using bacteria after preexposure to CLR, AMK, or TIG for 24 h and constructed isogenic knockout and knockdown strains. To assess strain specificity, pan-genome analysis of 35 strains from all three subspecies was performed. Mycobacterium abscessus shows both drug-specific and common transcriptomic responses to antibiotic exposure. Ribosome-targeting antibiotics CLR, AMK, and TIG elicit a common response characterized by upregulation of ribosome structural genes, the WhiB7 regulon and transferases, accompanied by downregulation of respiration through NuoA-N. Exposure to any of these drugs decreases susceptibility to ribosome-targeting drugs from multiple classes. The cytochrome bd-type quinol oxidase contributes to CFZ tolerance in M. abscessus, and the sigma factor sigH but not antisigma factor MAB_3542c is involved in TIG resistance. The observed transcriptomic responses are not strain-specific, as all genes involved in tolerance, except erm(41), are found in all included strains. |
| Databáze: | OpenAIRE |
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