Doble, A. C.; Gollan, B. C.; Clark-Corrigall, J. L.; Bulmer, D.; Daniel, R. A.; Mastroeni, P.; Khan, C. M. A.

The increased spread of multidrug-resistant bacteria no longer sensitive to commonly used antibiotics poses a major threat to human health. The search for potential new drug targets is critical in disease control and prevention. Whilst several components of the cell wall synthesis machinery are already targeted by beta-lactam antibiotics, other elements of this machinery present opportunities for novel drug targets. Landmark studies revealed RodA exhibits peptidoglycan polymerase activity in Bacillus subtilis and Escherichia coli, highlighting RodA as a prime for the next generation of antimicrobial drugs. However, the role of RodA in virulence remains unexplored. Through targeted mutagenesis, virulence gene reporter assays, and phenotypic screening, we demonstrate that the presence of RodA or PBP2, is intrinsically linked to the regulation of virulence gene expression in Salmonella. Specifically, deletion of either of these components causes both disruption in cell morphology and a complete downregulation in major cell invasion-associated virulence factors in vitro, and attenuated virulence in vivo. Significantly, this study highlights the importance of RodA and PBP2 in both the biology and virulence of an important bacterial pathogen, identifying them as promising targets for developing new antibiotics.