bedaquiline
Mechanisms of ResistanceThe TetR Family Transcription Factor MAB_2299c Regulates the Expression of Two Distinct MmpS-MmpL Efflux Pumps Involved in Cross-Resistance to Clofazimine and Bedaquiline in Mycobacterium abscessusMycobacterium abscessus is a human pathogen responsible for severe respiratory infections, particularly in patients with underlying lung disorders. Notorious for being highly resistant to most antimicrobials, new therapeutic approaches are needed to successfully treat M. abscessus-infected patients...
Mechanisms of Action: Physiological EffectsTBAJ-876 Retains Bedaquiline’s Activity against Subunits c and ε of Mycobacterium tuberculosis F-ATP SynthaseThe antituberculosis drug bedaquiline (BDQ) inhibits Mycobacterium tuberculosis F-ATP synthase by interfering with two subunits. Drug binding to the c subunit stalls the rotation of the c ring, while binding to the ε subunit blocks coupling of c ring rotation to ATP synthesis at the catalytic α3:β3 headpiece. BDQ is used for the treatment of drug...
Mechanisms of Action: Physiological EffectsVerapamil Improves the Activity of Bedaquiline against Mycobacterium abscessus In Vitro and in MacrophagesDue to intrinsic multidrug resistance, pulmonary infections with Mycobacterium abscessus are extremely difficult to treat. Previously, we demonstrated that bedaquiline is highly effective against Mycobacterium abscessus both in vitro and in vivo. Here, we report that verapamil...
Mechanisms of ResistanceAcquisition of Cross-Resistance to Bedaquiline and Clofazimine following Treatment for Tuberculosis in PakistanWe report on the first six cases of acquired resistance to bedaquiline in Pakistan. Seventy sequential isolates from 30 drug-resistant-tuberculosis patients on bedaquiline-containing regimens were retrospectively tested for bedaquiline resistance by MIC testing and by the detection of mutations in relevant genes. We documented cases failing therapy that developed specific mutations in Rv0678 and had increased MICs associated...
Mechanisms of ResistanceIn Vitro Study of Stepwise Acquisition of rv0678 and atpE Mutations Conferring Bedaquiline ResistanceBedaquiline resistance within Mycobacterium tuberculosis may arise through efflux-based (rv0678) or target-based (atpE) pathway mutations. M. tuberculosis mutant populations from each of five sequential steps in a passaging approach, using a pyrazinamide-resistant ATCC strain, were...
SusceptibilityIn Vitro Activity of Bedaquiline and Delamanid against Nontuberculous Mycobacteria, Including Macrolide-Resistant Clinical IsolatesWe evaluated the in vitro activities of the antimicrobial drugs bedaquiline and delamanid against the major pathogenic nontuberculous mycobacteria (NTM). Delamanid showed high MIC values for all NTM except Mycobacterium kansasii. However, bedaquiline showed low MIC values for the major pathogenic NTM, including...
Editor's Pick Mechanisms of Action: Physiological EffectsBedaquiline Eliminates Bactericidal Activity of β-Lactams against Mycobacterium abscessusThe β-lactams imipenem and cefoxitin are used for the treatment of Mycobacterium abscessus lung infections. Here, we show that these cell wall synthesis inhibitors trigger a lethal bacterial ATP burst by increasing oxidative phosphorylation. Cotreatment of M. abscessus with the antimycobacterial ATP...
SusceptibilityIn Vitro Activities of Bedaquiline and Delamanid against Nontuberculous Mycobacteria Isolated in Beijing, ChinaDue to the natural resistance of nontuberculous mycobacteria (NTM) against multiple antibiotics, treatment of infections caused by them is often long-course and less successful. The main objective of our study was the evaluation of in vitro susceptibility of 209 isolates consisting of different NTM species against bedaquiline and delamanid. Furthermore, reference strains of 33 rapidly growing mycobacterium (RGM) species and 19...
Experimental TherapeuticsShortening Buruli Ulcer Treatment with Combination Therapy Targeting the Respiratory Chain and Exploiting Mycobacterium ulcerans Gene DecayBuruli ulcer is treatable with antibiotics. An 8-week course of rifampin (RIF) and either streptomycin (STR) or clarithromycin (CLR) cures over 90% of patients.
Experimental TherapeuticsContribution of Pretomanid to Novel Regimens Containing Bedaquiline with either Linezolid or Moxifloxacin and Pyrazinamide in Murine Models of TuberculosisNovel regimens combining bedaquiline and pretomanid with either linezolid (BPaL regimen) or moxifloxacin and pyrazinamide (BPaMZ regimen) shorten the treatment duration needed to cure tuberculosis (TB) in BALB/c mice compared to that of the first-line regimen and have yielded promising results in initial clinical trials. However, the independent contribution of the investigational new drug pretomanid to the efficacy of BPaMZ has not...