We have entered the “era of resistance” marked by rapid global spread of genes that confer resistance to commonly used antibiotics, including the last-resort drug colistin. More than three million antibiotic-resistant infections occur in the U.S. each year, and more than 35,000 are fatal. Infections by multidrug resistant Gram-negative pathogens are of particular concern. Antibiotic-resistance genes (ARGs) are frequently encoded on conjugative plasmids which can be easily transferred between bacteria. Advances in surveillance and sequencing produced a wealth of information about plasmids encoding ARGs, treatment outcomes, co-occurrence with other resistance determinants, etc. However, little is known about the regulation of plasmid transfer that underlies this threat.
Expression of long transfer operons is energetically costly – bacteria silence them until needed, but turn them on to allow conjugation. We recently published a model in which histone-like NAPs and RfaH-like proteins silence and counter-silence extended chromosomal operons, respectively, and identified homologs of these genes on laboratory and clinical plasmids.
In collaboration with Will Navarre and Peter Freddolino, we are using R6K plasmid, which encodes NAP and RfaH homologs to investigate how these plasmid-encoded regulators control conjugation and how they interact with cellular factors. While R6K is an E. coli laboratory model, similar plasmids have been identified in clinical Klebsiella pneumoniae isolates. We expect that our findings could lead to discovery of small molecules that block ARG dissemination.