A Mycobacterium tuberculosis NBTI DNA Gyrase Inhibitor Is Active against Mycobacterium abscessus

Abstract

Fluoroquinolones – the only clinically used DNA gyrase inhibitors – are effective against tuberculosis (TB) but are in limited clinical use for non-tuberculous mycobacteria (NTM) lung infections due to intrinsic drug resistance. We sought to test alternative DNA gyrase inhibitors for anti-NTM activity. Mycobacterium tuberculosis Gyrase Inhibitors (MGIs), a subclass of Novel Bacterial Topoisomerase Inhibitors (NBTIs), were recently shown to be active against the tubercle bacillus. Here, we show that the MGI EC/11716 not only has potent anti-tubercular activity but is active against M. abscessus and M. avium in vitro . Focusing on M. abscessus , which causes the most difficult to cure NTM disease, we show that EC/11716 is bactericidal, active against drug-tolerant biofilms, and efficacious in a murine model of M. abscessus lung infection. Based on resistant mutant selection experiments, we report a low frequency of resistance to EC/11716 and confirm DNA gyrase as its target. Our findings demonstrate the potential of NBTIs as anti- M. abscessus and possibly broad spectrum anti-mycobacterial agents.

Activity of Tricyclic Pyrrolopyrimidine Gyrase B Inhibitor against Mycobacterium abscessus

“…TPP8 was administered intraperitoneally once daily for 10 consecutive days at 25 and 12.5 mg/kg, starting one day post-infection. Two comparator agents were used in the efficacy study: the phosphate prodrug form of SPR719, SPR720 (20), administered orally at 100 mg/kg, and moxifloxacin administered orally at 200 mg/kg (11), the efficacious dose in TB mouse models (20). Clarithromycin as positive control was administered orally at 250 mg/kg (11).…”

“…Two comparator agents were used in the efficacy study: the phosphate prodrug form of SPR719, SPR720 (20), administered orally at 100 mg/kg, and moxifloxacin administered orally at 200 mg/kg (11), the efficacious dose in TB mouse models (20). Clarithromycin as positive control was administered orally at 250 mg/kg (11). All mice were euthanized 24h after the last dose, and bacterial load in the lungs and spleen was determined by plating serial dilutions of organ homogenates on Middlebrook 7H11 agar.…”

“…Despite M. abscessus resistance to most approved anti-TB drugs, we found that compound collections of TB actives provide a good source for hit identification (6). Screening series of advanced TB actives against M. abscessus identified several compounds with in vivo activity, including inhibitors of RNA polymerase (7), ATP synthase (8), Leucyl-tRNA synthetase (9, 10), DNA gyrase (11) and DNA clamp DnaN (12). Expanding on this strategy, we asked whether the recently identified novel class of tricyclic pyrrolopyrimidines (TPPs (13)), targeting DNA gyrase in Mycobacterium tuberculosis and various other bacteria (14, 15) is active against M. abscessus .…”

“…synthetase (9,10), DNA gyrase (11) and DNA clamp DnaN (12). Expanding on this strategy, we asked whether the recently identified novel class of tricyclic pyrrolopyrimidines (TPPs (13)), targeting DNA gyrase in Mycobacterium tuberculosis and various other bacteria (14,15) is active against M. abscessus.…”

Cyclohexyl-griselimycin Is Active against Mycobacterium abscessus in Mice

“…Prioritization of advanced TB leads avoids the high attrition encountered in early lead optimization due to failure to introduce favorable PK properties and thus should accelerate the drug discovery process for M. abscessus . To leverage these advances, we screened TB leads against M. abscessus and identified several novel anti- M. abscessus compounds with demonstrated in vivo activity, including inhibitors of ATP synthase ( 8 ), leucyl tRNA synthetase ( 9 , 10 ), and DNA gyrase ( 11 ). Expanding on this strategy, we asked whether the recently identified preclinical anti-TB candidate cyclohexyl-griselimycin (CGM) ( 12 ) is active against M. abscessus .…”