Network Analysis Reveals Sex- and Antibiotic Resistance-Associated Antivirulence Targets in Clinical Uropathogens

Abstract

Increasing antibiotic resistance among uropathogenic Escherichia coli (UPEC) is driving interest in therapeutic targeting of nonconserved virulence factor (VF) genes. The ability to formulate efficacious combinations of antivirulence agents requires an improved understanding of how UPEC deploy these genes. To identify clinically relevant VF combinations, we applied contemporary network analysis and biclustering algorithms to VF profiles from a large, previously characterized inpatient clinical cohort. These mathematical approaches identified four stereotypical VF combinations with distinctive relationships to antibiotic resistance and patient sex that are independent of traditional phylogenetic grouping. Targeting resistance- or sex-associated VFs based upon these contemporary mathematical approaches may facilitate individualized anti-infective therapies and identify synergistic VF combinations in bacterial pathogens.

Enterobacteria secrete an inhibitor of Pseudomonas virulence during clinical bacteriuria

“…These results suggest that the early stages of ascending UTI are competitive and favor isolates with specific siderophore profiles. In this and other studies, Ybt, a siderophore encoded by the Yersinia high pathogenicity island (HPI), was associated with urinary tract virulence (7,(13)(14)(15)(16)(17).…”

“…Members of the family Enterobacteriaceae, particularly E. coli, inhabit the intestinal microbiome and are most commonly associated with asymptomatic bacteriuria and UTI. The early bacteriuric state from which UTIs can develop is poorly understood and challenging to study, but it is known that UTI-associated E. coli isolates frequently possess nonconserved genetic systems related to virulence (7,8).…”

“…Prominent among virulence-associated adaptations in uropathogenic E. coli (UPEC) isolates are siderophores, specialized metabolites able to bind extracellular Fe(III) ions for nutritional use in low-iron conditions (7,9). High-affinity Fe(III) binding by siderophores helps bacteria resist host-mediated iron deprivation, a prototypical example of nutritional immunity (10,11).…”

The Yersiniabactin-Associated ATP Binding Cassette Proteins YbtP and YbtQ Enhance Escherichia coli Fitness during High-Titer Cystitis

“…The Yersinia HPI is nearly ubiquitous among model uropathogenic E. coli strains, is associated with fluoroquinolone resistance when present in combination with the aerobactin siderophore system, and is typically present in over 70% of clinical urinary isolates (3,11,12). The Yersinia HPI encodes the yersiniabactin (Ybt) siderophore system, including yersiniabactin biosynthetic enzymes, in addition to outer and inner membrane transporters associated with metal-yersiniabactin complex import (13-16).…”

“…The Yersinia HPI encodes the yersiniabactin (Ybt) siderophore system, including yersiniabactin biosynthetic enzymes, in addition to outer and inner membrane transporters associated with metal-yersiniabactin complex import (13)(14)(15)(16). Yersiniabactin is one of three genetically nonconserved E. coli siderophore types (yersiniabactin, salmochelin, and aerobactin) that may be expressed in addition to enterobactin, the conserved E. coli siderophore (3,11,12). The Yersinia HPI is central to multiple E. coli urovirulence strategies, raising the possibility that it is functionally distinct from other siderophore systems (12).…”