Delamanid Kills Dormant Mycobacteria In Vitro and in a Guinea Pig Model of Tuberculosis

Abstract

Tuberculosis (TB) treatment is long and requires multiple drugs, likely due to various phenotypes of TB bacilli with variable drug susceptibilities. Drugs with broad activity are urgently needed. This study aimed to evaluate delamanid's activity against growing or dormant bacilli in vitro as well as in vivo. Cultures of Mycobacterium bovis BCG Tokyo under aerobic and anaerobic conditions were used to study the activity of delamanid against growing and dormant bacilli, respectively. Delamanid exhibited significant bactericidal activity against replicating and dormant bacilli at or above concentrations of 0.016 and 0.4 mg/liter, respectively. To evaluate delamanid's antituberculosis activity in vivo, we used a guinea pig model of chronic TB infection in which the lung lesions were similar to those in human TB disease. In the guinea pig TB model, a daily dose of 100 mg delamanid/kg of body weight for 4 or 8 weeks demonstrated strong bactericidal activity against Mycobacterium tuberculosis. Importantly, histological examination revealed that delamanid killed TB bacilli within hypoxic lesions of the lung. The combination regimens containing delamanid with rifampin and pyrazinamide or delamanid with levofloxacin, ethionamide, pyrazinamide, and amikacin were more effective than the standard regimen (rifampin, isoniazid, and pyrazinamide). Our data show that delamanid is effective in killing both growing and dormant bacilli in vitro and in the guinea pig TB model. Adding delamanid to current TB regimens may improve treatment outcomes, as demonstrated in recent clinical trials with pulmonary multidrug-resistant (MDR) TB patients. Delamanid may be an important drug for consideration in the construction of new regimens to shorten TB treatment duration. KEYWORDS Mycobacterium tuberculosis, delamanid, dormant, guinea pigT uberculosis (TB) remains one of the world's deadliest communicable diseases (1). TB is caused by Mycobacterium tuberculosis, an acid-fast bacillus that is transmitted primarily via the respiratory route. Although TB is treatable, the duration of treatment is at least 6 months for fully drug-susceptible TB with the 4 standard first-line drugs (i.e., isoniazid, rifampin, pyrazinamide, and ethambutol). The emergence of multidrugresistant (MDR) and extensively drug-resistant (XDR) mycobacterial strains and the epidemic of HIV/AIDS coinfections further complicate treatment (2). Even for uncomplicated MDR-TB treatment, current World Health Organization guidelines mandate at least 9 to 12 months of treatment with four or more second-line TB drugs with weaker activity and higher toxicity than the first-line drugs (3,4). Several factors of the host and pathogen and interactions between them are thought to contribute to the difficulty of treating TB (5, 6). One such factor is the existence of dormancy; some bacilli replicate very slowly or not at all and have the ability to tolerate chemotherapy. The reasons underlying bacterial persistence are complex, but some environmental conditions, such

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“…Given the high proportion of HHCs that have diagnosed TB or evidence of TBI, it is urgent that novel, preventive therapies are carefully studied. There are 2 trials now underway to assess fluoroquinolones in adults/adolescents (V-QUIN ACTRN12616000215426/U1111-1177-9052) and in children (TB CHAMP ISRCTN92634082), and our team is initiating a trial assessing the novel agent delamanid (PHOENIx NCT03568383), which has the potential added advantage of treating contacts of fluoroquinolone-resistant TB [1,29,30].…”

Adduct Formation of Delamanid with NAD in Mycobacteria

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Recent advances for identification of new scaffolds and drug targets for Mycobacterium tuberculosis

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