Colistin Resistance in Acinetobacter baumannii Is Mediated by Complete Loss of Lipopolysaccharide Production

By Jennifer H. Moffatt, M. Harper, P. Harrison, J. Hale, E. Vinogradov, Torsten Seemann, R. Henry, B. Crane, F. St. Michael, A. Cox and 4 more. Antimicrobial Agents and Chemotherapy, 2010

777 citations recorded by the source corpus.

ABSTRACT Infections caused by multidrug-resistant (MDR) Gram-negative bacteria represent a major global health problem. Polymyxin antibiotics such as colistin have resurfaced as effective last-resort antimicrobials for use against MDR Gram-negative pathogens, including Acinetobacter baumannii. Here we show that A. baumannii can rapidly develop resistance to polymyxin antibiotics by complete loss of the initial binding target, the lipid A component of lipopolysaccharide (LPS), which has long been considered to be essential for the viability of Gram-negative bacteria. We characterized 13 independent colistin-resistant derivatives of A. baumannii type strain ATCC 19606 and showed that all contained mutations within one of the first three genes of the lipid A biosynthesis pathway: lpxA, lpxC, and lpxD. All of these mutations resulted in the complete loss of LPS production. Furthermore, we showed that loss of LPS occurs in a colistin-resistant clinical isolate of A. baumannii. This is the first report of a spontaneously occurring, lipopolysaccharide-deficient, Gram-negative bacterium.

Subfields: Genetics, Molecular Medicine, Pharmacology

View Paper: https://www.semanticscholar.org/paper/0080af1c8fafa05489c91f506528cabd782a9ffc

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In Genetics

1. P. Nordmann
2. L. Poirel

In Molecular Medicine

1. L. Poirel
2. P. Nordmann
3. Jung Hun Lee
4. Chang-Ro Lee
5. B. Jeong
6. S. Lee
7. Kwang Seung Park
8. A. Potron

In Pharmacology

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Citations in the corpus

• Biology of Acinetobacter baumannii: Pathogenesis, Antibiotic Resistance Mechanisms, and Prospective Treatment Options (2017, background): “baumannii to many clinical important antibiotics, such as colistin (Moffatt et al., 2010; Arroyo et al., 2011; Beceiro et al., 2011; Pelletier et al., 2013; Boll et al., 2015; Chin et al., 2015).”
• Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria (2014, neutral): “The second is the complete loss of LPSs caused by either mutations or the insertional inactivation of lipid A biosynthesis genes (Moffatt et al., 2010, 2011).”
• Antimicrobial Resistance and Virulence: a Successful or Deleterious Association in the Bacterial World? (2013, background): “Similar alterations in the MICs caused by LPS modification have been observed in other studies (190).”
• Emerging broad-spectrum resistance in Pseudomonas aeruginosa and Acinetobacter baumannii: Mechanisms and epidemiology. (2015, background): “baumannii: (i) alterations of the lipid A component of LPS resulting from mutations in the PmrAB two-component system [304,305]; and (ii) complete loss of LPS production resulting from mutations in the lpxA, lpxC and lpxD genes encoding the enzymes that catalyse the first steps in LPS biosynthesis [”
• Polymyxins: Antibacterial Activity, Susceptibility Testing, and Resistance Mechanisms Encoded by Plasmids or Chromosomes (2017, background): “substitutions, truncations, frameshifts (109), or insertional inactivation by the insertion sequence ISAba11 (181).”