Maturing Mycobacterial Peptidoglycan Required Non-canonical Crosslinks to Maintain Shape

Baranowski, C.; Sham, L.-T.; Eskandarian, H. A.; Welsh, M. A.; Lim, H. C.; Kieser, K. J.; Wagner, J. C.; Walker, S.; McKinney, J. D.; Fantner, G. E.; Ioerger, T. R.; Bernhardt, T. G.; Rubin, E. J.; Rego, E. H.

doi:10.1101/291823

bioRxiv · 10.1101/291823

Maturing Mycobacterial Peptidoglycan Required Non-canonical Crosslinks to Maintain Shape

Baranowski, C.·Sham, L.-T.·Eskandarian, H. A.·Welsh, M. A.·Lim, H. C.·Kieser, K. J.·Wagner, J. C.·Walker, S.·McKinney, J. D.·Fantner, G. E.·Ioerger, T. R.·Bernhardt, T. G.·Rubin, E. J.·Rego, E. H.

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Abstract

In most well studied rod-shaped bacteria, peptidoglycan is primarily crosslinked by penicillin binding proteins (PBPs). However, in mycobacteria, L,D-transpeptidase (LDT)-mediated crosslinks are highly abundant. To elucidate the role of these unusual crosslinks, we characterized mycobacterial cells lacking all LDTs. We find that LDT-mediated crosslinks 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 single-cell distribution of drug targets can be exploited to more effectively treat this pathogen.

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Baranowski, C., Sham, L.-T., Eskandarian, H. A., Welsh, M. A., Lim, H. C., Kieser, K. J., Wagner, J. C., Walker, S., McKinney, J. D., Fantner, G. E., Ioerger, T. R., Bernhardt, T. G., Rubin, E. J., Rego, E. H.. 2018-03-30. Maturing Mycobacterial Peptidoglycan Required Non-canonical Crosslinks to Maintain Shape. https://doi.org/10.1101/291823

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