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A Penicillin-Binding Protein Inhibits Selection of Colistin-Resistant

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A Penicillin-Binding Protein Inhibits Selection of Colistin-Resistant A penicillin-binding protein inhibits selection of PNAS PLUS colistin-resistant, lipooligosaccharide-deficient Acinetobacter baumannii Joseph M. Bolla,b, Alexander A. Croftsa, Katharina Petersc, Vincent Cattoird, Waldemar Vollmerc, Bryan W. Daviesa,e, and M. Stephen Trentb,1 aDepartment of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712; bDepartment of Infectious Diseases, Center for Vaccines and Immunology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602; cCentre for Bacterial Cell Biology, Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE2 4AX, United Kingdom; dDepartment of Microbiology, Centre Hospitalier Universitaire de Caen, 14033 Caen Cedex 9, France; and eInstitute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712 Edited by Thomas J. Silhavy, Princeton University, Princeton, NJ, and approved August 23, 2016 (received for review July 14, 2016) The Gram-negative bacterial outer membrane fortifies the cell tidoglycan (via Nod receptors) chemical structures are PAMPs that against environmental toxins including antibiotics. Unique glyco- stimulate immune pathways to clear the bacterial infection (2, 3). To lipids called lipopolysaccharide/lipooligosaccharide (LPS/LOS) are circumvent detection by the host immune system, many Gram-neg- enriched in the cell-surface monolayer of the outer membrane and ative pathogens alter structural motifs on the cell surface by adding promote antimicrobial resistance. Colistin, which targets the lipid A chemical moieties to the lipid A domain of LPS/LOS. Not only does domain of LPS/LOS to lyse the cell, is the last-line treatment for camouflaging PAMPs offer protection from host innate immune multidrug-resistant Gram-negative infections. Lipid A is essential for detection, but also chemical modification of lipid A enhances re- the survival of most Gram-negative bacteria, but colistin-resistant sistance to many antimicrobial agents (4). Consequently, bacterial Acinetobacter baumannii lacking lipid A were isolated after colistin remodeling of outer-membrane lipid A limits the effective antimi- exposure. Previously, strain ATCC 19606 was the only A. baumannii strain demonstrated to subsist without lipid A. Here, we show that crobial arsenal to counteract Gram-negative bacterial infections. other A. baumannii strains can also survive without lipid A, but Acinetobacter baumannii is an emerging Gram-negative MICROBIOLOGY some cannot, affording a unique model to study endotoxin essen- pathogen that has quickly become pervasive throughout clinics tiality. We assessed the capacity of 15 clinical A. baumannii isolates and hospitals because it adapts to harsh environmental condi- including 9 recent clinical isolates to develop colistin resistance tions and quickly develops resistance to antimicrobials. Multi- through inactivation of the lipid A biosynthetic pathway, the prod- drug resistant A. baumannii isolates, especially those resistant ucts of which assemble the LOS precursor. Our investigation deter- to carbapenems, have been isolated (5–7). Currently, colistin mined that expression of the well-conserved penicillin-binding (polymyxin E) is prescribed as the last-resort antimicrobial to protein (PBP) 1A, prevented LOS-deficient colony isolation. The gly- treat multidrug resistant A. baumannii infections. Colistin is a cosyltransferase activity of PBP1A, which aids in the polymerization cationic lipopeptide that binds the negatively charged lipid A of the peptidoglycan cell wall, was lethal to LOS-deficient A. bau- phosphate groups to perturb the membrane and kill the bac- mannii. Global transcriptomic analysis of a PBP1A-deficient mutant terial cell. However, A. baumannii has also evolved colistin and four LOS-deficient A. baumannii strains showed a concomitant resistance mechanisms (8–11). increase in transcription of lipoproteins and their transporters. Ex- A. baumannii amination of the LOS-deficient cell surface demon- Significance strated 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 Antimicrobial drug resistance is a major threat to public health. resistance mechanism. Gram-negative bacteria are exceptionally resistant to antibiotics because of their outer-membrane barrier. Glycolipids called li- popolysaccharide (LPS) or lipooligosaccharide (LOS) fortify the Acinetobacter | peptidoglycan | colistin | lipoprotein | lipopolysaccharide outer membrane from many antimicrobials and biocides and were thought to be essential for Gram-negative bacterial sur- he bacterial cell envelope is a multifaceted structure that vival. The last-resort treatment for multidrug-resistant Gram- Tregulates uptake of essential nutrients and cofactors while negative infections is colistin, which targets the lipid A domain protecting the cell from its often-hostile environment. The de- of LPS/LOS to disrupt the membrane, but the emerging patho- fining feature of Gram-negative bacteria is an essential second gen Acinetobacter baumannii can develop colistin resistance by (outer) membrane in the cell envelope that encases the periplasm inactivating lipid A biosynthesis. This analysis advances our and peptidoglycan cell wall. The outer membrane forms a unique understanding of lipid A/LOS essentiality in A. baumannii and asymmetrical lipid bilayer barrier that enhances resistance to a identifies antimicrobial targets. variety of antibiotics and host immune mechanisms. Whereas the inner monolayer of the outer membrane is composed of glycer- Author contributions: J.M.B., A.A.C., K.P., W.V., B.W.D., and M.S.T. designed research; J.M.B., ophospholipids, the cell surface-exposed monolayer is enriched in A.A.C., K.P., W.V., B.W.D., and M.S.T. performed research; J.M.B., A.A.C., K.P., V.C., W.V., l p s l o s B.W.D., and M.S.T. contributed new reagents/analytic tools; J.M.B., A.A.C., K.P., V.C., W.V., either ipo oly accharide (LPS) or ipo ligo accharide (LOS), B.W.D., and M.S.T. analyzed data; and J.M.B., A.A.C., K.P., W.V., B.W.D., and M.S.T. wrote which are amphipathic glycolipids synthesized from the essential the paper. precursor, lipid A. The lipid A domain anchors LPS/LOS into the The authors declare no conflict of interest. outer membrane, whereas the hydrophilic components including This article is a PNAS Direct Submission. the core polysaccharides and O-polysaccharide(s) (in the case of Data deposition: The data discussed in this publication have been deposited in the Na- LPS) extend into the extracellular milieu (1). tional Center for Biotechnology’s Gene Expression Omnibus (accession no. GSE84282). Host immune receptors recognize pathogen-associated molecular 1To whom correspondence should be addressed. Email: [email protected]. p atterns (PAMPs) in the bacterial cell envelope during infection. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. The highly conserved lipid A (via TLR4/MD2 receptors) and pep- 1073/pnas.1611594113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1611594113 PNAS Early Edition | 1of10 Downloaded by guest on September 25, 2021 A. baumannii amplifies colistin resistance through modification of or lpxD, which encode the first three steps in the conserved lipid A the LOS lipid A anchor domain using three mechanisms. (i) Similar biosynthetic pathway. Characterization of a single lpxA mutant to lipid A modification strategies described in other Gram-negative confirmed that ATCC 19606 A. baumannii survived without LOS pathogens (4), A. baumannii enzymatically adds phosphoethanol- and its precursor, lipid A (12). To determine if survival without LOS amine and/or galactosamine to lipid A to enhance antibiotic re- is a characteristic of only strain ATCC 19606 (12) or all A. bau- sistance (8–10). Incorporation of amine-containing chemical moieties mannii strains, 15 clinical isolates including four multidrug re- neutralizes electrostatic interactions and reduces colistin binding to sistant strains were plated on colistin (10 μg/mL), and isolated lipid A in the outer membrane. (ii) Whereas many bacterial path- colonies were analyzed to determine the frequency of LOS inacti- ogens respond to cellular assaults through acyl chain addition to the vation. As shown in Table 1, 9 of the 15 strains (60%) propagated lipid A domain, A. baumannii encodes a mechanism that constitu- LOS-deficient A. baumannii after colistin exposure (as determined tively hyper-acylates the lipid A domain, presumably to alter host by colistin resistance/vancomycin sensitivity assays described here) immune recognition and to strengthen the outer-membrane barrier with a mutation frequency comparable to previously published (11). (iii) A. baumannii has also demonstrated a unique capacity to analysis (12). Importantly, six strains did not yield LOS-deficient inactivate the lipid A biosynthetic pathway to develop resistance to colistin-resistant colonies, demonstrating that some A. baumannii colistin (12). In this work, we show that lipid A inactivation results clinical isolates could not survive without LOS (Table 1). not only in colistin resistance, but also in cross-resistance to other To ensure that colistin-resistant A. baumannii did not produce clinically important antibiotics. lipid A, three isolates were further characterized including the A. baumannii is one of only three Gram-negative bacteria known previously described
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