Weak link in TB bacteria cell wall

The Mycobacterium tuberculosis protein LdtM2, involved in making “nonclassical” crosslinks in the bacterial cell wall, is required for virulence and antibiotic resistance. The study results, published online in Nature Medicine, could help identify new treatment combinations to tackle chronic tuberculosis infections.

Tuberculosis is a major global health threat. Drug resistance in TB is becoming a monumental problem and the very nature of the treatment schedule—usually a combination of four anti-TB drugs taken daily for six months—directly contributes to this problem. The majority of the TB bacteria are killed within the first two weeks of treatment but the remaining “persisters” need six months or more of treatment to effectively kill them. If this drug regime is misused or mismanaged then multidrug resistant and extensively drug resistant (XDR) strains of M. tuberculosis can develop …you only have to watch this slideshow of James Nachtwey’s photographs for XDRTB.org to see for yourself the devastating effects of XDR-TB.

Gupta and colleagues investigated the role of the M. tuberculosis cell wall in chronic TB infection—the physiology of which is poorly understood in the persistent stationary phase of bacterial growth. They examined the M. tuberculosis gene MT2594 (renamed in this paper ldtM2), which is a L,D-transpeptidase that helps create the “nonclassical” 3→3 crosslinks in the bacterial cell wall—a process which helps give the cell wall strength.

The researchers found that mutants lacking ldtM2 had an altered colony morphology compared with the wild-type strain—small, smooth, tower block-like colonies growing up from the agar surface into the air compared with the larger, rougher and flatter colonies of the wild-type. By making the mutants express ldtM2 again, they successfully restored the wild-type growth phenotype. They then infected mice with these mutant TB bacteria to see whether LdtM2 was important for bacterial virulence. After four weeks, mice were heavily infected with the wild-type and complemented bacterial strains and subsequently died, however, mice infected with ldtM2 mutant did not die nor were they significantly ill despite having bacteria present in their lungs. Moreover, during chronic TB infection in mice, ldtM2 mutants were more susceptible than wild-type bacteria to the antibiotic amoxicillin, in combination with clavulanate—added to inhibit the natural β-lactamases produced by TB bacteria, which normally allow the bacteria to resist the effects of β-lactam antibiotics like amoxicillin.

The authors suggest that the unusual 3→3 crosslinks made by the LdtM2 L,D-transpeptidase are “vital to the physiology of the peptidoglycan layer” and that these linkages, along with the classical 4→3 crosslinks, are involved in “maintaining and remodelling” the cell wall of the TB bacteria. Interestingly, this new data indicates that a combination of drugs to inhibit the L,D-transpeptidases and β-lactamases produced by TB bacteria could effectively kill the persistent bacteria that contribute  to chronic TB infection—something that would be most welcome on World TB day today.

ResearchBlogging.orgGupta, R., Lavollay, M., Mainardi, J., Arthur, M., Bishai, W., & Lamichhane, G. (2010). The Mycobacterium tuberculosis protein LdtMt2 is a nonclassical transpeptidase required for virulence and resistance to amoxicillin Nature Medicine DOI: 10.1038/nm.2120

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Filed under Infectious Disease, Medicine, Public Health

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