Bacterial pathogens exploit various molecular mechanisms to survive unpredictable and adverse environmental conditions. Gram-negative bacteria often alter their environmentally exposed outer membrane, an asymmetric bilayer consisting of inner leaflet glycerophospholipids and essential outer leaflet lipooligosaccharide (LPS) or lipopolysaccharide (LOS). Acinetobacter baumannii is a Gram-negative nosocomial pathogen that thrives in healthcare settings because of its ability to develop resistance to antibiotics. Multidrug resistant A. baumannii have become widespread over the past decade and last-line antibiotics such as colistin, which target the essential LOS in the outer membrane, have been increasingly prescribed to treat multidrug resistant infections. While colistin resistance was once rare, this is no longer the case, especially regarding A. baumannii. Uniquely, A. baumannii can completely shutdown LOS biosynthesis to develop resistance to colistin and many other commonly prescribed antibiotics. This finding is surprising since LPS/LOS are typically essential for Gram-negative bacterial viability. Mechanisms that contribute to LOS deficiency and the resulting multidrug resistance phenotype are not understood. The overall objective of this proposal is to characterize and understand a novel multidrug resistance mechanism.
The Specific Aims of this proposal are (i) to understand the genetic requirements for complete loss of LOS and (ii) to characterize the altered outer membrane permeability barrier in LOS deficient A. baumannii. Completion of this work will contribute a critical body of knowledge to the essentiality of LPS/LOS in Gram-negative bacteria and provide understanding of the molecular mechanisms required for a novel multidrug resistance mechanism. The basic science framework from this proposal could also potentially lead to development of novel therapeutics and improved vaccines.

Public Health Relevance

Increased prescription of last-line antibiotics has led to the emergence of multidrug resistant bacteria, a daunting threat to public health. The Aims of this proposal are to characterize a novel multidrug resistance mechanism providing the basic science framework for future antimicrobial treatment options.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI119879-03
Application #
9090098
Study Section
Prokaryotic Cell and Molecular Biology Study Section (PCMB)
Program Officer
Ernst, Nancy Lewis
Project Start
2015-06-15
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Georgia
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
Powers, Matthew Joseph; Trent, M Stephen (2018) Expanding the paradigm for the outer membrane: Acinetobacter baumannii in the absence of endotoxin. Mol Microbiol 107:47-56
Henderson, Jeremy C; Zimmerman, Shawn M; Crofts, Alexander A et al. (2016) The Power of Asymmetry: Architecture and Assembly of the Gram-Negative Outer Membrane Lipid Bilayer. Annu Rev Microbiol 70:255-78
Boll, Joseph M; Crofts, Alexander A; Peters, Katharina et al. (2016) A penicillin-binding protein inhibits selection of colistin-resistant, lipooligosaccharide-deficient Acinetobacter baumannii. Proc Natl Acad Sci U S A 113:E6228-E6237
Cullen, T W; Schofield, W B; Barry, N A et al. (2015) Gut microbiota. Antimicrobial peptide resistance mediates resilience of prominent gut commensals during inflammation. Science 347:170-5