Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States
Lok-To Sham
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States; Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore
School of Life Sciences, Swiss Federal Institute of Technology in Lausanne, Lausanne, Switzerland; School of Engineering, Swiss Federal Institute of Technology in Lausanne, Lausanne, Switzerland
Hoong Chuin Lim
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States
Karen J Kieser
Department of Immunology and Infectious Disease, Harvard TH Chan School of Public Health, Boston, United States
Jeffrey C Wagner
Department of Immunology and Infectious Disease, Harvard TH Chan School of Public Health, Boston, United States
John D McKinney
School of Life Sciences, Swiss Federal Institute of Technology in Lausanne, Lausanne, Switzerland
Georg E Fantner
School of Engineering, Swiss Federal Institute of Technology in Lausanne, Lausanne, Switzerland
Thomas R Ioerger
Department of Computer Science and Engineering, Texas A&M University, Texas, United States
Suzanne Walker
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States
Department of Immunology and Infectious Disease, Harvard TH Chan School of Public Health, Boston, United States; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States
In most well-studied rod-shaped bacteria, peptidoglycan is primarily crosslinked by penicillin-binding proteins (PBPs). However, in mycobacteria, crosslinks formed by L,D-transpeptidases (LDTs) are highly abundant. To elucidate the role of these unusual crosslinks, we characterized Mycobacterium smegmatis cells lacking all LDTs. We find that crosslinks generate by LDTs are required for rod shape maintenance specifically at sites of aging cell wall, a byproduct of polar elongation. Asymmetric polar growth leads to a non-uniform distribution of these two types of crosslinks in a single cell. Consequently, in the absence of LDT-mediated crosslinks, PBP-catalyzed crosslinks become more important. Because of this, Mycobacterium tuberculosis (Mtb) is more rapidly killed using a combination of drugs capable of PBP- and LDT- inhibition. Thus, knowledge about the spatial and genetic relationship between drug targets can be exploited to more effectively treat this pathogen.
