Nonclassical Transpeptidases of Mycobacterium tuberculosis Alter Cell Size, Morphology, the Cytosolic Matrix, Protein Localization, Virulence, and Resistance to β-Lactams

Virtually all bacteria possess a peptidoglycan layer that is essential for their growth and survival. The β-lactams, the most widely used class of antibiotics in human history, inhibitd,d -transpeptidases, which catalyze the final step in peptidoglycan biosynthesis. The existence of a second class of transpeptidases, thel,d -transpeptidases, was recently reported.Mycobacterium tuberculosis , an infectious pathogen that causes tuberculosis (TB), is known to possess as many as five proteins withl,d -transpeptidase activity. Here, for the first time, we demonstrate that loss ofl,d -transpeptidases 1 and 2 ofM. tuberculosis (LdtMt1 and LdtMt2 ) alters cell surface morphology, shape, size, organization of the intracellular matrix, sorting of some low-molecular-weight proteins that are targeted to the membrane or secreted, cellular physiology, growth, virulence, and resistance ofM. tuberculosis to amoxicillin-clavulanate and vancomycin.