Crystal structure of L,D-transpeptidase Ldt_Mt2 in complex with meropenem reveals the mechanism of carbapenem against Mycobacterium tuberculosis

Tuberculosis (TB), an infectious disease caused by the bacillus Mycobacterium tuberculosis, leads to substantial mortality worldwide¹. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis has challenged conventional anti-TB therapy and threatens global disease control of TB^2,3. The development of new anti-TB drugs is urgently required⁴. β-lactams are effective antibiotics widely used to treat bacterial infections; however, so far no effective anti-TB antibiotics have emerged from this class of drugs. Previous studies have indicated that an important reason for the lack of effective β-lactam anti-TB antibiotics is the presence of a chromosomally-encoded class A (Ambler) β-lactamase, BlaC, in M. tuberculosis⁵.

A recent study by Hugonnet et al.⁶ has demonstrated that a combination of meropenem-clavulanate was effective against 13 XDR strains of M. tuberculosis. Meropenem is a member of the carbapenem class of β-lactams and contains a bicyclic nucleus, a pyrroline ring and a β-lactam ring, and clavulanate is a β-lactamase inhibitor. Both are FDA-approved drugs and could potentially be used to treat TB, providing a novel clinical treatment strategy⁶. However, the bactericidal mechanism of this drug combination in treating TB is unclear. Hugonnet et al. suggest that one reason for the efficacy of the meropenem-clavulanate combination against XDR strains is that meropenem is poorly hydrolyzed by BlaC⁶.

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