Reinforcing the barrier: Understanding how cell envelope modifications promote intrinsic antimicrobial tolerance and resistance in Acinetobacter baumannii

Project Summary/Abstract
Emergence of multidrug and extensively drug resistant Gram-negative bacteria is a growing problem that threatens
established antimicrobial treatment protocols. Acinetobacter baumannii is an emerging critical threat pathogen
notorious for its ability to rapidly develop intrinsic multidrug resistance. A. baumannii causes hospital-acquired
infections, which manifest as bacteremia, urinary tract and wound infections. In the US, an estimated 60% of
hospital-acquired A. baumannii infections were multidrug resistant, often including carbapenem resistance, which
leaves colistin as the “last-resort” treatment option. However, colistin resistance has also emerged. There is an
urgent need to understand intrinsic mechanisms that promote antibiotic resistance phenotypes in A. baumannii to
guide alternative antimicrobial strategies. Our preliminary work has identified factors that promote acquisition of
multidrug resistance, including carbapenem and colistin resistance, in A. baumannii. Specifically, links between the
outer membrane and peptidoglycan layers of the cell envelope are key for the resistance phenotypes, where one
layer compensates for defects in the other. While enzymes that assemble the outer membrane and cell wall are
largely known, A. baumannii encodes unique regulatory mechanisms to control their activity in response to stress.
In this proposal, we will address three important questions to understand intrinsic antibiotic resistance in A.
baumannii. The questions will explore the relationship between peptidoglycan and outer membrane assembly, which
is poorly understood in Gram-negative bacteria. Findings from this work will enable us to build a model of intrinsic
factors in A. baumannii that lead to multidrug resistance and will help in the design of combinatorial drug regimens
that target both essential layers, thus precluding resistance; consequently, our findings support the National
Institute of Health mission, which aims to foster fundamental discoveries to reduce human disease.

Grant Number: 5R35GM143053-06
NIH Institute/Center: NIH
Principal Investigator: Joseph Boll