Reversion of antibiotic resistance in Mycobacterium tuberculosis by spiroisoxazoline SMARt-420

Abstract

Antibiotic resistance is one of the biggest threats to human health globally. Alarmingly, multidrug-resistant and extensively drug-resistant have now spread worldwide. Some key antituberculosis antibiotics are prodrugs, for which resistance mechanisms are mainly driven by mutations in the bacterial enzymatic pathway required for their bioactivation. We have developed drug-like molecules that activate a cryptic alternative bioactivation pathway of ethionamide in, circumventing the classic activation pathway in which resistance mutations have now been observed. The first-of-its-kind molecule, named SMARt-420 (Small Molecule Aborting Resistance), not only fully reverses ethionamide-acquired resistance and clears ethionamide-resistant infection in mice, it also increases the basal sensitivity of bacteria to ethionamide.

EthA/R-Independent Killing of Mycobacterium tuberculosis by Ethionamide

“…Furthermore, they confirm the importance of MshA pathway and mycothiol in ETH killing efficacy, and may suggest a role of this pathway at a later step, after formation of the ETH cidal metabolite, ETH ∗ . Hence, together with the recent discovery of an alternative BVMO (MymA) capable of activating ETH (Grant et al, 2016), and a cryptic alternative pathway of ETH bio-activation (Blondiaux et al, 2017), our findings underscore the complexity and possible redundancy of the mechanisms involved in ETH bio-activation in pathogenic mycobacteria. Greater understanding of these mechanisms and their possible cross-talks are necessary in order to rationally design intervention strategies to improve ETH killing efficacy.…”

“…This alternative pathway of ETH bio-activation that is functional in MTB but not in BCG is likely to be distinct from the cryptic operon ( rv0077c-rv0078 ) recently reported by Blondiaux et al (2017), which is only expressed in the presence of small molecules that inhibit the EthR-like repressor (Rv0078), thereby allowing expression of ethA2 gene ( rv0077c ) which encodes an EthA-like monooxigenase capable of activating ETH.…”

“…More recently, another mycobacterial Baeyer–Villiger monooxygenase, MymA, was reported to be able to activate ETH, as evidenced by increased MIC 90 of ETH in mymA -overexpressing MTB and increased resistance to ETH in loss-of-function mymA mutants (Grant et al, 2016). Even more recently, a cryptic alternative bio-activation pathway of ETH has been reported which consists of a bicistronic divergent operon ( rv0077c-rv0078 ) sharing homologies with the ethA/R locus although no cross-talk between the two regulons could be demonstrated (Blondiaux et al, 2017). …”

Eine strukturelle Evaluierung medizinalchemischer Strategien gegen Wirkstoffresistenzen

“…[22] Ethionamid (3,Abbildung 4) ist ein Wirkstoffvorläufermolekül, das in die aktive Form 4 durch die Monooxygenase EthA im Bakterium umgewandelt werden muss. [22] Ethionamid (3,Abbildung 4) ist ein Wirkstoffvorläufermolekül, das in die aktive Form 4 durch die Monooxygenase EthA im Bakterium umgewandelt werden muss.…”

Counter resistance

“…Interest has grown recently in devising strategies to reverse or overcome resistance and enable a drug that is ineffective to kill once again. In a recent example, Alain Baulard and colleagues developed compounds that could help to overcome resistance against the second-line TB drug ethionamide (ETH) 2 . ETH requires bioactivation by M. tuberculosis to convert it from prodrug to active form, making ETH vulnerable to mutations occurring in ethA, which encodes the monooxygenase responsible for activating the prodrug.…”