Essential Roles of RodA Peptidoglycan Polymerase and PBP2 Transpeptidase in Expression of Cell Wall-Spanning Supramolecular Organelles and Modulating Salmonella Virulence

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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.

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  1. Thank you very much for this important paper and for making it available to everyone as an open-access pre-print! I'm always really excited to find new research on bacterial cell wall biology, especially as it pertains to its contribution to virulence. I was wondering if I could ask a question about the rod-to-sphere morphological transition that you have observed in Salmonella upon disruption of cell wall enzymes. Specifically in Salmonella, is there a strong correlation between having a sphere morphology and a decrease in virulence? Are there any exceptions to this? Are there mutants with a sphere morphology that show an increase in virulence? Thank you very much for your time! And congratulations once more!