Verapamil Improves the Activity of Bedaquiline against Mycobacterium abscessusIn Vitro and in Macrophages

Viljoen, Albertus; Raynaud, Clément; Johansen, Matt D.; Roquet-Banères, Françoise; Herrmann, Jean-Louis; Daher, Wassim; Kremer, Laurent

doi:10.1128/aac.00705-19

Cited by 21 publications

(14 citation statements)

References 27 publications

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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%

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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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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“…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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“…Two studies reported poor or negative results for BDQ administration against nontuberculous mycobacteria-infected patients (27,28). However, recent studies showed that the activity of BDQ can be potentiated with adjunctive therapy, thus improving BDQ-based treatments (16,29). This study provides evidence that treatment with the BDQ-IPM combination remains superior to treatment with IPM alone and equivalent to that with BDQ alone, as judged by the comparable bacterial clearance in the spleens of the mice treated with BDQ-IPM versus BDQ alone.…”

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confidence: 99%

Efficacy of Bedaquiline, Alone or in Combination with Imipenem, against Mycobacterium abscessus in C3HeB/FeJ Mice

Moigne

Raynaud

Moreau

et al. 2020

Antimicrob Agents Chemother

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Mycobacterium abscessus lung infections remain difficult to treat. Recent studies have recognized the power of new combinations of antibiotics, such as bedaquiline and imipenem, although in vitro data have questioned this combination. We report that the efficacy of bedaquiline-imipenem combination treatment relies essentially on the activity of bedaquiline in a C3HeB/FeJ mice model of infection with a rough variant of M. abscessus. The addition of imipenem contributed to clearing the infection in the spleen.

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Verapamil Improves the Activity of Bedaquiline against Mycobacterium abscessusIn Vitro and in Macrophages

Cited by 21 publications

References 27 publications

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

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?

Efficacy of Bedaquiline, Alone or in Combination with Imipenem, against Mycobacterium abscessus in C3HeB/FeJ Mice

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