Rifampicin (RIF) resistance is a risk factor for poor outcome in tuberculosis (TB). In Mycobacterium tuberculosis, both target gene mutation and efflux pumps have major roles in the resistance to anti-TB drugs. This study aimed to determine whether RIF induces efflux pump activation in RIF-monoresistant M. tuberculosis strains. Here, we took advantage of 16 RIF-monoresistant M. tuberculosis clinical isolates to evaluate the expression of 27 putative drug efflux pump genes and measured the influence of four drug efflux pump inhibitors, carbonyl cyanide m-chlorophenyl hydrazone (CCCP), verapamil (VP), thioridazine (TZ) and chlorpromazine (CPZ), on the RIF MICs of these strains. Eight of the 16 RIF-monoresistant isolates carried mutations in rpoB and overexpressed one or two of the following putative efflux pump genes: Rv2333, drrB, drrC, Rv0842, bacA and efpA. CCCP, VP, TZ and CPZ lowered the RIF MICs greater than fourfold in 6, 12, 9 and 12 isolates, respectively. The lowered RIF MICs by VP and CPZ were identical and stronger than CCCP (P-values were all 0.033). In conclusion, the efflux pumps Rv2333, DrrB, DrrC, Rv0842, BacA and EfpA may have a role in RIF resistance in addition to classical mutations in the rpoB gene, and the addition of VP and CPZ could significantly increase RIF susceptibility in RIF-monoresistant M. tuberculosis.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1038/ja.2015.9 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Identification and characterisation of two functional antibiotic MATE efflux pumps in the archaeon Halorubrum amylolyticum.
NPJ Antimicrob Resist
August 2024
Biofilm Research Group, School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK.
Multidrug efflux pumps have been found to play a crucial role in drug resistance in bacteria and eukaryotes. In this study, we investigated the presence of functional multidrug and toxic compound extrusion (MATE) efflux pumps, inferred from whole genome sequencing, in the halophilic archaeon Halorubrum amylolyticum CSM52 using Hoechst 33342 dye accumulation and antimicrobial sensitivity tests in the presence and absence of efflux pump inhibitors (EPIs). The whole genome sequence of H.
View Article and Find Full Text PDFMultidrug efflux in Gram-negative bacteria: structural modifications in active compounds leading to efflux pump avoidance.
NPJ Antimicrob Resist
March 2024
Computational Biology, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Gram-negative bacteria cause the majority of critically drug-resistant infections, necessitating the rapid development of new drugs with Gram-negative activity. However, drug design is hampered by the low permeability of the Gram-negative cell envelope and the function of drug efflux pumps, which extrude foreign molecules from the cell. A better understanding of the molecular determinants of compound recognition by efflux pumps is, therefore, essential.
View Article and Find Full Text PDFAddressing Data Point Homogeneity and Annotation Challenges to Enhance Data-Driven Approaches: The S. aureus NorA Efflux Pump Case Study.
ChemMedChem
January 2025
University of Perugia: Universita degli Studi di Perugia, Department of Pharmaceutical Sciences, ITALY.
In this study, we analyzed publicly accessible data related to the Staphylococcus aureus NorA protein, a well-known efflux pump involved in antimicrobial resistance. Our analysis revealed several inconsistencies in data annotation, and significant issues concerning the homogeneity across datasets, which compromise the reliability of data-driven approaches aimed at identifying novel Staphylococcus aureus NorA efflux pump inhibitors (EPIs). To address these challenges, we propose a standardized pipeline for experimental procedures and data annotation, designed to enhance the consistency and quality of EPI datasets submitted to repositories, thereby increasing the utility of publicly available datasets for the discovery of potential EPIs.
View Article and Find Full Text PDFTetracycline and chloramphenicol exposure induce decreased susceptibility to tigecycline and genetic alterations in AcrAB-TolC efflux pump regulators in Escherichia coli and Klebsiella pneumoniae.
PLoS One
January 2025
Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
Tigecycline (Tgc), a third-generation tetracycline is found as the last line of defense against multi-drug resistant bacteria. Recent increased rate of resistance to tgc, a human-restricted agent among animal bacteria poses a significant global health challenge. Overuse of first generation tetracyclines (Tet) and phenicols in animals have been suggested to be associated with Tgc resistance development.
View Article and Find Full Text PDFDiscovery and biological evaluation of nitrofuranyl-pyrazolopyrimidine hybrid conjugates as potent antimicrobial agents targeting and methicillin-resistant .
RSC Med Chem
December 2024
Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine Canal Road Jammu-180001 India
Nitrofuran and pyrazolopyrimidine-based compounds possess a broad antimicrobial spectrum including Gram-positive and Gram-negative bacteria. In the present work, a series of conjugates of these scaffolds was synthesized and evaluated for antimicrobial activity against and methicillin-resistant (MRSA). Many compounds showed MIC values of ≤2 μg ml, with compound 35 demonstrating excellent activity (MICs: 0.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!