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bioRxiv · 10.1101/2020.09.16.300541

Inhibition of Streptococcus pneumoniae autolysins highlight distinct differences between chemical and genetic inactivation

Haubrich, B. A.·Nayyab, S.·Williams, C.·Whitman, A.·Zimmerman, T.·Li, Q.·Chen, Y.·Zhou, C.-Z.·Basu, A.·Reid, C. W.
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Abstract

Despite renewed interest, development of chemical biology methods to study peptidoglycan metabolism has lagged in comparison to the glycobiology field in general. To address this, a panel of diamides were screened against the Gram-positive pathogen Streptococcus pneumoniae to identify inhibitors of bacterial growth. The screen identified the diamide fgkc as a narrow spectrum bacteriostatic inhibitor of S. pneumoniae growth with an MIC of 7.8 M. The diamide inhibited detergent-induced autolysis in a concentration dependent manner indicating peptidoglycan degradation as the mode-of-action. Genetic screening of autolysin mutants suggested LytB, an endo-N-acetylglucosaminidase, involved in cell division as the potential target. Surprisingly, biochemical, and phenotypic analysis contradicted the genetic screen results. Phenotypic studies with the{Delta} lytb strain illustrate the difference between genetic and chemical inactivation of autolysins. These findings suggest that meta-phenotypes including autolytic activity, cell morphology, and genetic screening can be the result of the complex interaction of one or more possible pathways that are connected to cell wall metabolism.

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Haubrich, B. A., Nayyab, S., Williams, C., Whitman, A., Zimmerman, T., Li, Q., Chen, Y., Zhou, C.-Z., Basu, A., Reid, C. W.. 2020-09-16. Inhibition of Streptococcus pneumoniae autolysins highlight distinct differences between chemical and genetic inactivation. https://doi.org/10.1101/2020.09.16.300541

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