A penicillin-binding protein inhibits selection of colistin-resistant, lipooligosaccharide-deficient Acinetobacter baumannii.
The Gram-negative bacterial outer membrane fortifies the cell against environmental toxins including antibiotics. Unique glycolipids called lipopolysaccharide/lipooligosaccharide (LPS/LOS) are enriched in the cell-surface monolayer of the outer membrane and promote antimicrobial resistance. Colistin, which targets the lipid A domain of LPS/LOS to lyse the cell, is the last-line treatment for multidrug-resistant Gram-negative infections. Lipid A is essential for the survival of most Gram-negative bacteria, but colistin-resistant Acinetobacter baumannii lacking lipid A were isolated after colistin exposure. Previously, strain ATCC 19606 was the only A. baumannii strain demonstrated to subsist without lipid A. Here, we show that other A. baumannii strains can also survive without lipid A, but some cannot, affording a unique model to study endotoxin essentiality. We assessed the capacity of 15 clinical A. baumannii isolates including 9 recent clinical isolates to develop colistin resistance through inactivation of the lipid A biosynthetic pathway, the products of which assemble the LOS precursor. Our investigation determined that expression of the well-conserved penicillin-binding protein (PBP) 1A, prevented LOS-deficient colony isolation. The glycosyltransferase activity of PBP1A, which aids in the polymerization of the peptidoglycan cell wall, was lethal to LOS-deficient A. baumannii Global transcriptomic analysis of a PBP1A-deficient mutant and four LOS-deficient A. baumannii strains showed a concomitant increase in transcription of lipoproteins and their transporters. Examination of the LOS-deficient A. baumannii cell surface demonstrated that specific lipoproteins were overexpressed and decorated the cell surface, potentially compensating for LOS removal. This work expands our knowledge of lipid A essentiality and elucidates a drug resistance mechanism.
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712; Department of Infectious Diseases, Center for Vaccines and Immunology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.
Joseph M
JM
Boll
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712.
Alexander A
AA
Crofts
Centre for Bacterial Cell Biology, Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE2 4AX, United Kingdom.
Katharina
K
Peters
Department of Microbiology, Centre Hospitalier Universitaire de Caen, 14033 Caen Cedex 9, France.
Vincent
V
Cattoir
Centre for Bacterial Cell Biology, Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE2 4AX, United Kingdom.
Waldemar
W
Vollmer
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712; Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712.
Bryan W
BW
Davies
Department of Infectious Diseases, Center for Vaccines and Immunology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602; strent@uga.edu.
M Stephen
MS
Trent
D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000235:genetics; D002462:Cell Membrane / Q000378:metabolism; D003091:Colistin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D005798:Genes, Bacterial; D008070:Lipopolysaccharides / Q000096:biosynthesis / Q000172:deficiency*; D008826:Microbial Sensitivity Tests; D046915:Penicillin-Binding Proteins / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D014158:Transcription, Genetic / Q000187:drug effects
D008070:Lipopolysaccharides; D046915:Penicillin-Binding Proteins; C023023:lipid-linked oligosaccharides; D003091:Colistin
Acinetobacter; colistin; lipopolysaccharide; lipoprotein; peptidoglycan
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