Examination of bedaquiline- and linezolid-resistant Mycobacterium tuberculosis isolates from the Moscow region

Zimenkov, Danila; Nosova, Elena; Kulagina, Elena V.; Антонова, О. В.; Arslanbaeva, Liaisan; Isakova, Alexandra I.; Krylova, L. Yu.; Peretokina, Irina V.; Makarova, Marina; Safonova, Svetlana; Borisov, S. E.; Gryadunov, Dmitry

doi:10.1093/jac/dkx094

Cited by 106 publications

(111 citation statements)

References 35 publications

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“…The proposed combination may jeopardize treatment options for those patients, particularly if failure strains are resistant to both second-line core drugs: bedaquiline and FLQ [37]. Indeed, some small studies of bedaquiline-containing regimens show high rates of acquired drug resistance to bedaquiline: 24 out of 116 tests in Russia [38], and 6 out of 30 in Pakistan [39]. An alternative approach, applying the cascade of regimens concept, seems a better option: in TB treatment regimens, the core drug should be rifampicin when the strain is susceptible to rifampicin, a later generation FLQ in case of resistance to rifampicin, and bedaquiline if there is a resistance to FLQ [14].…”

Section: Discussionmentioning

confidence: 99%

Short-Course Regimen for Multidrug-Resistant Tuberculosis: A Decade of Evidence

Trébucq

Decroo

Deun

et al. 2019

JCM

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About ten years ago, the first results of the so-called “Bangladesh regimen”, a short regimen lasting nine months instead of 20 months, revolutionized multidrug-resistant tuberculosis (MDR-TB) treatment. Similar short regimens were studied in different settings, relying for their efficacy on a later generation fluoroquinolone, either gatifloxacin, moxifloxacin, or levofloxacin. We review the published material on short MDR-TB regimens, describe their different compositions, their results in national tuberculosis programs in middle- and low-income countries, the risk of acquiring resistance to fluoroquinolone, and the occurrence of adverse events. With over 80% success, the regimen performs much better than longer regimens (usually around 50%). Monitoring of adverse events allows adapting its composition to prevent severe adverse events such as deafness. We discuss the current applicability and usefulness of the short injectable-containing regimen given the 2019 recommendation of the World Health Organization (WHO) for a new long all-oral regimen. We conclude that the most effective fluoroquinolone is gatifloxacin, currently not listed as an essential medicine by WHO. It is a priority to restore its status as an essential medicine.

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Section: Discussionmentioning

confidence: 99%

Short-Course Regimen for Multidrug-Resistant Tuberculosis: A Decade of Evidence

Trébucq

Decroo

Deun

et al. 2019

JCM

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“…This is reflected in studies which show that high levels of BDQ resistance (10-100-fold MIC) are conferred by in vitro isolated spontaneous c-subunit missense mutations [43,44]. The recent emergence of c-subunit resistance mutations in clinical isolates from BDQ-treated TB patients further affirms this notion [46].…”

Section: Stalling Of Rotation Of the Mycobacterial F-atp Synthase C-ringmentioning

confidence: 93%

Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline

2019

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Bedaquiline (BDQ) inhibits ATP generation in Mycobacterium tuberculosis by interfering with the F-ATP synthase activity. Two mechanisms of action of BDQ are broadly accepted. A direct mechanism involves BDQ binding to the enzyme's c-ring to block its rotation, thus inhibiting ATP synthesis in the enzyme's catalytic α 3 β 3 -headpiece. An indirect mechanism involves BDQ uncoupling electron transport in the electron transport chain from ATP synthesis at the F-ATP synthase. In a recently uncovered second direct mechanism, BDQ binds to the enzyme's ε-subunit to disrupt its ability to link c-ring rotation to ATP synthesis at the α 3 β 3 -headpiece. However, this mechanism is controversial as the drug's binding affinity for the isolated ε-subunit protein is moderate and spontaneous resistance mutants in the ε-subunit cannot be isolated. Recently, the new, structurally distinct BDQ analogue TBAJ-876 was utilized as a chemical probe to revisit BDQ's mechanisms of action. In this review, we first summarize discoveries on BDQ's mechanisms of action and then describe the new insights derived from the studies of TBAJ-876. The TBAJ-876 investigations confirm the c-ring as a target, while also supporting a functional role for targeting the ε-subunit. Surprisingly, the new findings suggest that the uncoupler mechanism does not play a key role in BDQ's anti-mycobacterial activity.Concentration (MIC) of 0.002-0.013 µg/mL [10,11]). This potent activity holds true in vivo where BDQ has demonstrated accelerated sterilizing activity [12], with four months of BDQ treatment being as efficacious as six months of first-line drug treatment of Mtb-infected mice [13]. Importantly, BDQ also displays bactericidal activity against non-replicating Mtb at therapeutically attainable concentrations [14,15]. In the clinical setting, the usage of BDQ has produced promising results. Studies have shown that the usage of the drug for drug-resistant TB treatment improved sputum conversion and reduced chemotherapy duration and relapse [16][17][18][19]. Hence, new BDQ-containing drug regimens are currently being explored in Phase III clinical trials, such as the STREAM and SimpliciTB trials [20]. One such trial, the Nix-TB trial, resulted in the recent US FDA approval of the BDQ-pretomanid-linezolid six months, all-oral regimen for the treatment of drug-resistant TB [21,22].

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“…In all likelihood, not all of the L3 mutations observed are relevant to antibiotic resistance, so the role of these mutations needs to be examined. The role of L3 mutations in M. tuberculosis resistance to LZD treatment has recently been verified (7)(8)(9). In this context, it should be emphasized that both the L3 sequence and the molecular interactions of L3 in the ribosome vary from one bacterium to another, so findings from one bacteria are not proof of the effect in others but do suggest the possibility of an effect and can support a suggested relationship.…”

Section: Discussionmentioning

confidence: 99%

“…The mutations correspond to mutations observed in pathogenic bacteria, and that study thus supports, in general, the presumed or proven effects from other studies. For example, an LZD resistance effect from L3 N149R in E. coli (6) correlates well with a resistance effect of the L3 C154R substitution in M. tuberculosis at the corresponding position (7)(8)(9).…”

mentioning

confidence: 88%

Combined Effect of the Cfr Methyltransferase and Ribosomal Protein L3 Mutations on Resistance to Ribosome-Targeting Antibiotics

Pakuła

Hansen

Vester

2017

Antimicrob Agents Chemother

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Several groups of antibiotics inhibit bacterial growth by binding to bacterial ribosomes. Mutations in ribosomal protein L3 have been associated with resistance to linezolid and tiamulin, which both bind at the peptidyl transferase center in the ribosome. Resistance to these and other antibiotics also occurs through methylation of 23S rRNA at position A2503 by the methyltransferase Cfr. The mutations in L3 and the cfr gene have been found together in clinical isolates, raising the question of whether they have a combined effect on antibiotic resistance or growth. We transformed a plasmid-borne cfr gene into a uL3-depleted Escherichia coli strain containing either wild-type L3 or L3 with one of seven mutations, G147R, Q148F, N149S, N149D, N149R, Q150L, or T151P, expressed from plasmid-carried rplC genes. The L3 mutations are well tolerated, with small to moderate growth rate decreases. The presence of Cfr has a very minor influence on the growth rate. The resistance of the transformants to linezolid, tiamulin, florfenicol, and Synercid (a combination of quinupristin and dalfopristin [Q-D]) was measured by MIC assays. The resistance from Cfr was, in all cases, stronger than the effects of the L3 mutations, but various effects were obtained with the combinations of Cfr and L3 mutations ranging from a synergistic to an antagonistic effect. Linezolid and tiamulin susceptibility varied greatly among the L3 mutations, while no significant effects on florfenicol and Q-D susceptibility were seen. This study underscores the complex interplay between various resistance mechanisms and cross-resistance, even from antibiotics with overlapping binding sites.KEYWORDS Cfr, L3 mutations, antibiotic resistance, linezolid resistance, tiamulin resistance O ver time, more and more mutations in bacterial ribosomal protein L3 (renamed uL3 in accordance with the new universal naming of ribosomal proteins [1]) have been associated with resistance to the antibiotics linezolid (LZD, an oxazolidinone) and tiamulin (TIA, a pleuromutilin). These drugs have overlapping binding sites at the peptidyl transferase center (PTC) in the ribosome (Fig. 1). Specific mutations of 23S rRNA and methylation at position 2503 also cause resistance to these antibiotics, as reviewed in references 2-4. The main part of L3 is positioned on the surface of the 50S ribosomal subunit, but a branched loop extends close to the PTC (Fig. 1), the binding site for various ribosomal antibiotics. The first L3 resistance mutation reported in bacteria was from Escherichia coli selected with TIA, and its role in resistance was verified by genetic evidence (5). Since then, L3 mutations have been associated with resistance to LZD, TIA/valnemulin, and anisomycin, as reviewed in references 2 and 6. Relationships between L3 mutations and antibiotic resistance have been reported in Brachyspira, Staphylococcus, E. coli, and Mycobacterium tuberculosis, but many of the findings lack genetic verification. Our recent study (6) demonstrated a clear antibiotic

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Examination of bedaquiline- and linezolid-resistant Mycobacterium tuberculosis isolates from the Moscow region

Abstract: The introduction of novel drugs into treatment must be accompanied by continuous phenotypic susceptibility testing and the analysis of genetic determinants of resistance.

Cited by 106 publications

References 35 publications

Short-Course Regimen for Multidrug-Resistant Tuberculosis: A Decade of Evidence

Short-Course Regimen for Multidrug-Resistant Tuberculosis: A Decade of Evidence

Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline

Combined Effect of the Cfr Methyltransferase and Ribosomal Protein L3 Mutations on Resistance to Ribosome-Targeting Antibiotics

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