Selected Publications

The impact of the extracellular environment on mechanisms of heteroresistance is unclear. Studying fosfomycin heteroresistance in an Enterobacter cloacae complex isolate, we observed that glucose availability greatly increased the frequency of the resistant subpopulation. Glucose downregulated the glycerol and fosfomycin importer GlpT, whose expression was heterogenous at the single cell level. This heterogeneous expression of GlpT, in combination with the expression of the fosfomycin resistance gene fosA, which acted as a resistance enhancer, led to the generation of heteroresistance. Correspondingly, the frequency of the fosfomycin resistant subpopulation was increased in murine models of hyperglycemia/diabetes. These data demonstrate how metabolic heterogeneity and carbon source availability can impact antibiotic resistance phenotypes in the infection environment.

We sought to uncover the mechanism of heteroresistance to cefiderocol, a novel β-lactam developed to resist β-lactamases including extended-spectrum-β-lactamases (ESBLs), which has been recently reported but poorly understood. We observe HR to cefiderocol among clinical isolates collected before its use. The resistant subpopulation in Enterobacter is a continuum; increasing copy number of a gene encoding an ESBL ineffective against cefiderocol mediates increased resistance in decreasing numbers of cells. We observe that ESBL activity correlates with the level of amplification, and thus that increased copy number can compensate for poor enzymatic activity.. These data provide insights into factors controlling dynamics of HR and how bacteria can use gene amplification to flexibly confront new antibiotic threats.

Hypervirulent Klebsiella pneumoniae (hvKp) has emerged as a concerning global pathogen. hvKp is more virulent than classical K. pneumoniae (cKp) and capable of causing community-acquired infections, often in healthy individuals. hvKp is carried in the gastrointestinal tract, which contributes to its spread in the community and healthcare settings. hvKp arose as a leading cause of pyogenic liver abscesses. In addition to liver abscesses, hvKp is distinct from cKp in its ability to metastasize to distant sites, including most commonly the eye, lung and central nervous system (CNS). The genetic determinants of hypervirulence are often found on large virulence plasmids as well as chromosomal mobile genetic elements which can be used as biomarkers to distinguish hvKp from cKp clinical isolates. These distinct virulence determinants of hvKp include up to four siderophore systems for iron acquisition, increased capsule production, K1 and K2 capsule types, and the colibactin toxin.  This review details the distinguishing features of hypervirulent K. pneumoniae