Breaking down walls

Abstract

A better understanding of the mechanisms underpinning the growth of mycobacteria could help identify targets for new antibiotics.

Keywords: Mycobacteria; antibiotics; cell wall; epidemiology; global health; infectious disease; microbiology; peptidoglycan; sidewall; tuberculosis.

Figure 1.. The synthesis and remodeling of peptidoglycan in mycobacteria during growth.

The cell wall of a mycobacterium consists of an outer capsule-like layer (teal line), mycolic acids (magenta line), arabinogalactan (purple line), peptidoglycan (green lines) and a bilayer of fatty acids comprising the cell membrane (orange line and circles with tails). These protect the cytoplasm, which is surrounded by the periplasm. Peptidoglycan is made from monomers that contain a sugar molecule (green hexagon) and a chain of three to five amino acids (different colored circles). Precursor peptidoglycan units are synthesized inside the cell and linked to a lipid carrier. These units are transported into the periplasm by an enzyme called a flippase. Crosslinks (brown lines) between the monomers lead to the formation of a rigid matrix that encases the cell. Garcia-Heredia et al. (left) used monopeptide and dipeptide FDAA probes (one and two pink circles respectively) to study both the synthesis of new peptidoglycan and the remodeling of existing peptidoglycan: the monopeptide probes can be incorporated into peptidoglycan (in the place of the amino acid D-Alanine) both inside and outside the cell, whereas the dipeptide probes can only be incorporated inside the cell. Previously, it was thought that growth in mycobacteria only happened at the poles, where peptidoglycan is active. However, the work of Garcia-Heredia et al. suggests that there is a gradient of peptidoglycan activity along the sidewall of the dividing mycobacterium, with a maximum (dark green) near the poles and a minimum (pale green) near the center, and that the synthesis and the remodeling can both occur at the sidewall. Baranowski et al. (right) confirm that the side wall contains active peptidoglycan. Moreover, they show that the crosslinks change from the 4–3 confirmation at the poles to the 3–3 confirmation at the sidewall. The 3–3 crosslinks are formed by enzymes called L,D-transpeptidases (LDTs); deleting these enzymes affects the activity of DacB2, an endopeptidase that can break down peptidoglycan, which leads to the formation of blebs (see inset) and damage to the cell wall. The 4–3 crosslinks are formed by an enzyme called PonA1, which is a D,D-transpeptidase. Taken together, these two studies provide a revised paradigm for peptidoglycan remodeling in mycobacteria that could help with the development of new drugs to target the mycobacteria that cause diseases such as tuberculosis.