Clofazimine Exposure
            <i>In Vitro</i>
            Selects Efflux Pump Mutants and Bedaquiline Resistance

Ismail, Nagwa Abdallah; Peters, Remco P. H.; Ismail, Nazir; Omar, Shaheed V.

doi:10.1128/aac.02141-18

Cited by 34 publications

(34 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also identified two important phenomena of clinical interest: cross-resistance and heteroresistance. Some mutations at Rv1979c, pepQ, and Rv0678 caused cross-resistance to clofazimine [21,28,34,35]. Additionally, all the genes identified for DLM resistance here (ddn, fgd1, fbiA, and fbiC) are also recognized molecular markers of pretomanid resistance [11].…”

Section: Other Findings: Mutations In Drug-susceptible Strains Crossmentioning

confidence: 99%

Whole Genome Sequencing for the Analysis of Drug Resistant Strains of Mycobacterium tuberculosis: A Systematic Review for Bedaquiline and Delamanid

2020

View full text Add to dashboard Cite

Tuberculosis (TB) remains the deadliest Infectious disease worldwide, partially due to the increasing dissemination of multidrug and extensively drug-resistant (MDR/XDR) strains. Drug regimens containing the new anti-TB drugs bedaquiline (BDQ) and delamanid (DLM) appear as a last resort for the treatment of MDR or XDR-TB. Unfortunately, resistant cases to these drugs emerged just one year after their introduction in clinical practice. Early detection of resistant strains to BDQ and DLM is crucial to preserving the effectiveness of these drugs. Here, we present a systematic review aiming to define all available genotypic variants linked to different levels of resistance to BDQ and DLM that have been described through whole genomic sequencing (WGS) and the available drug susceptibility testing methods. During the review, we performed a thorough analysis of 18 articles. BDQ resistance was associated with genetic variants in Rv0678 and atpE, while mutations in pepQ were linked to a low-level of resistance for BDQ. For DLM, mutations in the genes ddn, fgd1, fbiA, and fbiC were found in phenotypically resistant cases, while all the mutations in fbiB were reported only in DLM-susceptible strains. Additionally, WGS analysis allowed the detection of heteroresistance to both drugs. In conclusion, we present a comprehensive panel of gene mutations linked to different levels of drug resistance to BDQ and DLM.

show abstract

Section: Other Findings: Mutations In Drug-susceptible Strains Crossmentioning

confidence: 99%

Whole Genome Sequencing for the Analysis of Drug Resistant Strains of Mycobacterium tuberculosis: A Systematic Review for Bedaquiline and Delamanid

2020

View full text Add to dashboard Cite

show abstract

“… 8 Serial passage of Mycobacterium tuberculosis in vitro in the presence of clofazimine selects for development of Rv0678 variants conferring bedaquiline cross-resistance, suggesting that clinical clofazimine use could lead to bedaquiline resistance even without bedaquiline use. 9 Identification of resistance is limited by uncertainties over critical concentrations to differentiate resistant and susceptible isolates. The bedaquiline minimum inhibitory concentration (MIC) above which isolates are deemed resistant was set at 0·25 μg/mL on 7H11 agar, although some isolates with Rv0678 mutations have MICs at or below this concentration.…”

Section: Introductionmentioning

confidence: 99%

Population-level emergence of bedaquiline and clofazimine resistance-associated variants among patients with drug-resistant tuberculosis in southern Africa: a phenotypic and phylogenetic analysis

et al. 2020

View full text Add to dashboard Cite

Summary Background Bedaquiline and clofazimine are important drugs in the treatment of drug-resistant tuberculosis and are commonly used across southern Africa, although drug susceptibility testing is not routinely performed. In this study, we did a genotypic and phenotypic analysis of drug-resistant Mycobacterium tuberculosis isolates from cohort studies in hospitals in KwaZulu-Natal, South Africa, to identify resistance-associated variants (RAVs) and assess the extent of clofazimine and bedaquiline cross-resistance. We also used a comprehensive dataset of whole-genome sequences to investigate the phylogenetic and geographical distribution of bedaquiline and clofazimine RAVs in southern Africa. Methods In this study, we included M tuberculosis isolates reported from the PRAXIS study of patients with drug-resistant tuberculosis treated with bedaquiline (King Dinuzulu Hospital, Durban) and three other cohort studies of drug-resistant tuberculosis in other KwaZulu-Natal hospitals, and sequential isolates from six persistently culture-positive patients with extensively drug-resistant tuberculosis at the KwaZulu-Natal provincial referral laboratory. Samples were collected between 2013 and 2019. Microbiological cultures were done as part of all parent studies. We sequenced whole genomes of included isolates and measured bedaquiline and clofazimine minimum inhibitory concentrations (MICs) for isolates identified as carrying any Rv0678 variant or previously published atpE, pepQ , and Rv1979c RAVs, which were the subject of the phenotypic study. We combined all whole-genome sequences of M tuberculosis obtained in this study with publicly available sequence data from other tuberculosis studies in southern Africa (defined as the countries of the Southern African Development Community), including isolates with Rv0678 variants identified by screening public genomic databases. We used this extended dataset to reconstruct phylogenetic relationships across lineage 2 and 4 M tuberculosis isolates. Findings We sequenced the whole genome of 648 isolates from 385 patients with drug-resistant tuberculosis recruited into cohort studies in KwaZulu-Natal, and 28 isolates from six patients from the KwaZulu-Natal referral laboratory. We identified 30 isolates with Rv0678 RAVs from 16 (4%) of 391 patients. We did not identify any atpE, pepQ , or Rv1979c RAVs. MICs were measured for 21 isolates with Rv0678 RAVs. MICs were above the critical concentration for bedaquiline resistance in nine (43%) of 21 isolates, in the intermediate category in nine (43%) isolates, and within the wild-type range in three (14%) isolates. Clofazimine MICs i...

show abstract

“…In conclusion, we report the identification of a pump-based resistance mechanism to the spiroketal indolyl Mannich base lead SIMBL MmpL5-mediated resistance has been reported for multiple antimycobacterials (10,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28).…”

Section: Downloaded Frommentioning

confidence: 74%

“…Next, we tested the prediction that M1, M2 and B1 should display cross-resistance to other drugs subject to the MmpR5-MmpL5 resistance mechanism and chose bedaquiline as our test compound (16,(18)(19)(20)(21)(22)(23)(24)(25). The MIC 90 of bedaquiline against all three mutants was 6 to 8-fold higher compared to wild type (Table 2), thus demonstrating cross-resistance.…”

Section: Downloaded Frommentioning

confidence: 99%

Resistance against Membrane-Inserting MmpL3 Inhibitor through Upregulation of MmpL5 in Mycobacterium tuberculosis

Nyantakyi

et al. 2020

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Spiroketal indolyl Mannich bases (SIMBs) present a novel class of membrane-inserting antimycobacterials with efficacy in a tuberculosis mouse model. SIMBs exert their antibacterial activity by two mechanisms. The indolyl Mannich base scaffold causes permeabilization of bacteria and the spiroketal moiety contributes to inhibition of the mycolic acid transporter MmpL3. Here, we show that low-level resistance to SIMBs arises by mutations in the transcriptional repressor MmpR5 resulting in upregulation of the efflux pump MmpL5.

show abstract

Clofazimine Exposure In Vitro Selects Efflux Pump Mutants and Bedaquiline Resistance

Cited by 34 publications

References 15 publications

Whole Genome Sequencing for the Analysis of Drug Resistant Strains of Mycobacterium tuberculosis: A Systematic Review for Bedaquiline and Delamanid

Whole Genome Sequencing for the Analysis of Drug Resistant Strains of Mycobacterium tuberculosis: A Systematic Review for Bedaquiline and Delamanid

Population-level emergence of bedaquiline and clofazimine resistance-associated variants among patients with drug-resistant tuberculosis in southern Africa: a phenotypic and phylogenetic analysis

Resistance against Membrane-Inserting MmpL3 Inhibitor through Upregulation of MmpL5 in Mycobacterium tuberculosis

Contact Info

Product

Resources

About