High Prevalence of Bedaquiline Resistance in Treatment-Naive Tuberculosis Patients and Verapamil Effectiveness

Ghajavand, Hasan; Kamakoli, Mansour Kargarpour; Khanipour, Sharareh; Dizaji, Shahin Pourazar; Masoumi, Maryam; Jamnani, Fatemeh Rahimi; Fateh, Abolfazl; Siadat, Seyed Davar; Vaziri, Farzam

doi:10.1128/aac.02530-18

Cited by 44 publications

(41 citation statements)

References 22 publications

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“…This work provides a summarized panel of mutations linked to DLM and BDQ resistance detected through WGS. DLM and BDQ are currently distributed in a limited number of countries [62,63]; however, RAM in BDQ naïve Mtb strains have been already identified [30,35,37]. The latter suggests that BDQ/DLM Mtb-resistant strains could be circulating even in countries where these drugs have not been introduced yet.…”

Section: Discussionmentioning

confidence: 99%

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

2020

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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.

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Section: Discussionmentioning

confidence: 99%

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

2020

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“…Several reports showed that the most spreading mechanism of BDQ resistance in clinical setting is represented by mutations in Rv0678 gene even if with a low level of BDQ-resistance (Villellas et al, 2017;Nieto Ramirez et al, 2020). To fight BDQ-resistance caused by Rv0678 mutations and to allow its use for the largest possible part of patients, verapamil, an efflux inhibitor, could be the keystone, since it has been demonstrated to increase the efficacy of BDQ against both M. tuberculosis and Mycobacterium abscessus (Ghajavand et al, 2019;Viljoen et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…As responsible for BDQ resistance, mutations in the intergenic region between Rv0678 and MmpS5 as well as mutations in the genes encoding the efflux pump MmpS5/MmpL5 were also reported (Ghajavand et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

In vitro Study of Bedaquiline Resistance in Mycobacterium tuberculosis Multi-Drug Resistant Clinical Isolates

et al. 2020

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Tuberculosis (TB) is one of the major causes of death related to antimicrobial resistance worldwide because of the spread of Mycobacterium tuberculosis multi-and extensively drug resistant (multi-drug resistant (MDR) and extensively drug-resistant (XDR), respectively) clinical isolates. To fight MDR and XDR tuberculosis, three new antitubercular drugs, bedaquiline (BDQ), delamanid, and pretomanid were approved for use in clinical setting. Unfortunately, BDQ quickly acquired two main mechanisms of resistance, consisting in mutations in either atpE gene, encoding the target, or in Rv0678, coding for the repressor of the MmpS5-MmpL5 efflux pump. To better understand the spreading of BDQ resistance in MDR-and XDR-TB, in vitro studies could be a valuable tool. To this aim, in this work an in vitro generation of M. tuberculosis mutants resistant to BDQ was performed starting from two MDR clinical isolates as parental cultures. The two M. tuberculosis MDR clinical isolates were firstly characterized by whole genome sequencing, finding the main mutations responsible for their MDR phenotype. Furthermore, several M. tuberculosis BDQ resistant mutants were isolated by both MDR strains, harboring mutations in both atpE and Rv0678 genes. These BDQ resistant mutants were further characterized by studying their growth rate that could be related to their spreading in clinical settings. Finally, we also constructed a data sheet including the mutations associated with BDQ resistance that could be useful for the early detection of BDQ-resistance in MDR/XDR patients with the purpose of a better management of antibiotic resistance in clinical settings.

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“…Calcium antagonists improved in vitro activities of tetracycline and fluoroquinolones against S. aureus, Enterobacteriaceae and non-fermenters irrespective of whether the strains were tetracycline-or fluoroquinolone-resistant [158][159][160]. It also improved activities of ofloxacin, rifampicin, and bedaquilin, but not isoniazid or amikacin against M. tuberculosis as well as M. abscessus (Table 3) [ [161][162][163][164][165][166][167][168][169]. Verapamil also increased the intraphagocytic activities of isoniazid and rifampicin [168] as well as bedaquilin and moxifloxacin [168] against drug-susceptible and drug-resistant M. tuberculosis and also the intracellular activity of azithromycin against L. monocytogenes [170,171] and that of daptomycin against S. aureus [172].…”

Section: Calcium Channel Blockersmentioning

confidence: 99%

Are antibacterial effects of non-antibiotic drugs random or purposeful because of a common evolutionary origin of bacterial and mammalian targets?

Dalhoff

2020

Infection

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Purpose Advances in structural biology, genetics, bioinformatics, etc. resulted in the availability of an enormous pool of information enabling the analysis of the ancestry of pro- and eukaryotic genes and proteins. Methods This review summarizes findings of structural and/or functional homologies of pro- and eukaryotic enzymes catalysing analogous biological reactions because of their highly conserved active centres so that non-antibiotics interacted with bacterial targets. Results Protease inhibitors such as staurosporine or camostat inhibited bacterial serine/threonine or serine/tyrosine protein kinases, serine/threonine phosphatases, and serine/threonine kinases, to which penicillin-binding-proteins are linked, so that these drugs synergized with β-lactams, reverted aminoglycoside-resistance and attenuated bacterial virulence. Calcium antagonists such as nitrendipine or verapamil blocked not only prokaryotic ion channels but interacted with negatively charged bacterial cell membranes thus disrupting membrane energetics and inducing membrane stress response resulting in inhibition of P-glycoprotein such as bacterial pumps thus improving anti-mycobacterial activities of rifampicin, tetracycline, fluoroquinolones, bedaquilin and imipenem-activity against Acinetobacter spp. Ciclosporine and tacrolimus attenuated bacterial virulence. ACE-inhibitors like captopril interacted with metallo-β-lactamases thus reverting carbapenem-resistance; prokaryotic carbonic anhydrases were inhibited as well resulting in growth impairment. In general, non-antibiotics exerted weak antibacterial activities on their own but synergized with antibiotics, and/or reverted resistance and/or attenuated virulence. Conclusions Data summarized in this review support the theory that prokaryotic proteins represent targets for non-antibiotics because of a common evolutionary origin of bacterial- and mammalian targets resulting in highly conserved active centres of both, pro- and eukaryotic proteins with which the non-antibiotics interact and exert antibacterial actions.

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High Prevalence of Bedaquiline Resistance in Treatment-Naive Tuberculosis Patients and Verapamil Effectiveness

Cited by 44 publications

References 22 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

In vitro Study of Bedaquiline Resistance in Mycobacterium tuberculosis Multi-Drug Resistant Clinical Isolates

Are antibacterial effects of non-antibiotic drugs random or purposeful because of a common evolutionary origin of bacterial and mammalian targets?

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