Acinetobacter Metabolism in Infection and Antimicrobial Resistance

Abstract

Acinetobacter infections have high rates of mortality due to an increasing incidence of infections by multidrug-resistant (MDR) and extensively-drug-resistant (XDR) strains. Therefore, new therapeutic strategies for the treatment of Acinetobacter infections are urgently needed. Acinetobacter spp. are Gram-negative coccobacilli that are obligate aerobes and can utilize a wide variety of carbon sources. Acinetobacter baumannii is the main cause of Acinetobacter infections, and recent work has identified multiple strategies A. baumannii uses to acquire nutrients and replicate in the face of host nutrient restriction. Some host nutrient sources also serve antimicrobial and immunomodulatory functions. Hence, understanding Acinetobacter metabolism during infection may provide new insights into novel infection control measures. In this review, we focus on the role of metabolism during infection and in resistance to antibiotics and other antimicrobial agents and discuss the possibility that metabolism may be exploited to identify novel targets to treat Acinetobacter infections.

Keywords: A. baumannii; Acinetobacter; antibiotic resistance; antimicrobial; antimicrobial resistance; infection; metabolism; nutrients.

FIG 1

Central carbon metabolism in pathogenic Acinetobacter. The gray arrow indicates that gluconolactone can be nonenzymatically hydrolyzed to gluconate and the enzyme is not typically encoded in A. baumannii and closely related species. Abbreviations: PQQH2, reduced pyrroloquinoline quinone; 6PG, 6-phosphogluconate; KDGP, 2-keto-3-deoxy-6-phosphogluconate; G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; FBP, fructose-1,6-bisphosphate; E4P, erythrose-4-phosphate; S7P, sedulose-7-phosphate; X5P, xylose-5-phosphate; Ri5P, ribulose-5-phosphate; R5P, ribose-5-phosphate; G3P, glyceraldehyde-3-phosphate; DHAP, dihydroxyacetone phosphate; BPG, 1,3-bisphosphoglycerate; 3PG, 3-phosphoglycerate; 2PG, 2-phosphoglycerate; PEP, phosphoenolpyruvate; GLX, glyoxylate.

FIG 2

Host-mediated nutrient metal restriction and intoxication during A. baumannii infection. (Left side) Metal restriction. Host innate immune cells such as neutrophils release calprotectin, which binds zinc, manganese, iron, and nickel, limiting pathogen access. A. baumannii imports manganese and zinc with MumT and Znu transporters. Urea metabolism is coordinated with the response to manganese restriction and helps resist calprotectin. A. baumannii relies on the siderophore acinetobactin to acquire iron during infection, and in some sites, acinetobactin iron acquisition is disrupted by host release of lipocalin-2. Acinetobactin also helps A. baumannii competitively inhibit growth of commensal microbiota members. A. baumannii can also utilize heme and ferrous iron transport system Feo to acquire iron. (Right side) Metal intoxication. The host also imposes metal intoxication on invading A. baumannii, likely after phagocytosis. A. baumannii fights copper intoxication with the CopA efflux protein and CueO multicopper oxidase. Excess zinc depletes A. baumannii copper, and A. baumannii resists zinc intoxication with the Czc efflux proteins.

FIG 3

Long-chain fatty acids mediate opposing effects during A. baumannii infection. A. baumannii desaturases DesA/B and phospholipase D (Pld) are critical during infection. During inflammatory bursts immune cells such as neutrophils can release polyunsaturated fatty acids (PUFAs) that inhibit bacteria, including A. baumannii. A. baumannii β-oxidation can help combat PUFA toxicity. Host monounsaturated fatty acids can inhibit A. baumannii quorum sensing and biofilm formation.

FIG 4

Catabolism of organic acids and amine compounds promotes A. baumannii virulence. A. baumannii encodes carnitine import protein Aci01347, which is required for growth on carnitine as the sole carbon and energy source. Histidine catabolism is encoded by pathogenic Acinetobacter spp., and HutH is required for utilization of histidine as a carbon and nitrogen source. Mutants lacking CarO are resistant to carbapenems and lose ornithine transport activity, suggesting CarO transports carbapenems and ornithine into the cell. Pathogenic Acinetobacter spp. can catabolize kynurenine (Kyn) with KynB and KynU. The γ-aminobutyric acid (GABA) aminotransferase GabT and the phenylacetic acid (PAA) pathway both contribute to resistance to reactive oxygen species (ROS). PAA catabolism also contributes to immune evasion, as mutants in the pathway excrete PAA, which serves as a neutrophil chemoattractant. Antibiotics promote expression of PAA pathway genes and inhibit chaperone-usher (Csu) pilus expression in a PAA-dependent mechanism. Host mucin glycoproteins can serve as the sole carbon and energy source for A. baumannii and promote paa gene expression.