2019
DOI: 10.1128/aac.02245-18
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Indole-2-Carboxamides Are Active against Mycobacterium abscessus in a Mouse Model of Acute Infection

Abstract: Nontuberculous mycobacteria (NTM) pathogens particularly infect patients with structural lung disorders. We previously reported novel indole-2-carboxamides (ICs) that are active against a wide panel of NTM pathogens. This study discloses in vivo data for two lead molecules (compounds 5 and 25) that were advanced for efficacy studies in Mycobacterium abscessus-infected mouse models. Oral administration of the lead molecules showed a statistically significant reduction in the bacterial loads in lung and spleen o… Show more

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Cited by 29 publications
(41 citation statements)
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“…Accordingly, a number of MmpL3 inhibitors are currently under development; among them, SQ109, 13 which has completed phase II efficacy studies in TB patients in Africa, and a number of indolecarboxamide- and tetrapyrazolopyrimidine-based inhibitors selected on the basis of their mycobactericidal activity, tolerability, favorable pharmacokinetic profiles and efficacy in acute and chronic murine models of TB and NTM infections. 68,1420 The lack of simple and relatively high-throughput assays to rapidly screen optimized analogues of these compounds currently represents an obstacle to their further development. The finding that some of these inhibitors have more than one target in Mtb (including other targets in the mycolic acid biosynthetic pathway) 16,21 together with the observation that a subset of them may exert their inhibitory effect on MmpL3 by dissipating the proton motive force (PMF) from which MmpL transporters derive their energy 2124 has further raised questions as to their direct or indirect mechanism of inhibition of MmpL3.…”
mentioning
confidence: 99%
“…Accordingly, a number of MmpL3 inhibitors are currently under development; among them, SQ109, 13 which has completed phase II efficacy studies in TB patients in Africa, and a number of indolecarboxamide- and tetrapyrazolopyrimidine-based inhibitors selected on the basis of their mycobactericidal activity, tolerability, favorable pharmacokinetic profiles and efficacy in acute and chronic murine models of TB and NTM infections. 68,1420 The lack of simple and relatively high-throughput assays to rapidly screen optimized analogues of these compounds currently represents an obstacle to their further development. The finding that some of these inhibitors have more than one target in Mtb (including other targets in the mycolic acid biosynthetic pathway) 16,21 together with the observation that a subset of them may exert their inhibitory effect on MmpL3 by dissipating the proton motive force (PMF) from which MmpL transporters derive their energy 2124 has further raised questions as to their direct or indirect mechanism of inhibition of MmpL3.…”
mentioning
confidence: 99%
“…These inhibitors have been shown to work by inhibiting the transfer of mycolic acids to their cell envelope acceptors in M. abs strains [92]. Further work has been done on this class of inhibitors; in 2019, Pandya et al reported that oral administration of the inhibitors shows a statistically significant reduction in bacterial load in the lungs and spleens of M. abs -infected mice [93].…”
Section: Future Perspectives For M Abscessusmentioning
confidence: 99%
“…Activity against clinical strains [42] Synergy with imipenem and cefoxitin [43] Intracellular effect in macrophages [42], effect in a murine model [44].…”
Section: N/a Indole-carboxamidesmentioning
confidence: 99%
“…Indole-carboxamides also act by disrupting mycolic acid transport and production, therefore inhibiting the synthesis of the mycobacterial cell wall [42]. Indole-carboxamides were shown to have a strong antibacterial activity against a wide panel of M. abscessus isolates in vitro and in infected macrophages [42], were shown to have synergistic effect with imipenem and cefoxitin [43] and were found active in a murine M. abscessus infection model [44]. No clinical trials are available for these experimental drugs.…”
Section: Novel Antimicrobialsmentioning
confidence: 99%