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Constraint-based modeling identifies new putative targets to fight colistin-resistant A. baumannii infections.

ABSTRACT: Acinetobacter baumannii is a clinical threat to human health, causing major infection outbreaks worldwide. As new drugs against Gram-negative bacteria do not seem to be forthcoming, and due to the microbial capability of acquiring multi-resistance, there is an urgent need for novel therapeutic targets. Here we have derived a list of new potential targets by means of metabolic reconstruction and modelling of A. baumannii ATCC 19606. By integrating constraint-based modelling with gene expression data, we simulated microbial growth in normal and stressful conditions (i.e. following antibiotic exposure). This allowed us to describe the metabolic reprogramming that occurs in this bacterium when treated with colistin (the currently adopted last-line treatment) and identify a set of genes that are primary targets for developing new drugs against A. baumannii, including colistin-resistant strains. It can be anticipated that the metabolic model presented herein will represent a solid and reliable resource for the future treatment of A. baumannii infections.

SUBMITTER: Presta L

PROVIDER: S-EPMC5473915 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundWith an increase in the use of colistin methansulfonate (CMS) to treat carbapenem-resistant Acinetobacter baumannii infections, colistin resistance is emerging.MethodsPatients with infection or colonization due to colistin-resistant A. baumannii were identified at a hospital system in Pennsylvania. Clinical data were collected from electronic medical records. Susceptibility testing, pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST) were performed. To investigate the mechanism of colistin resistance, lipid A was subjected to matrix-assisted laser desorption/ionization mass spectrometry.ResultsTwenty patients with colistin-resistant A. baumannii were identified. Ventilator-associated pneumonia was the most common type of infection. Nineteen patients had received intravenous and/or inhaled CMS for treatment of carbapenem-resistant, colistin-susceptible A. baumannii infection prior to identification of colistin-resistant isolates. The 30-day all-cause mortality rate was 30%. The treatment regimen for colistin-resistant A. baumannii infection associated with the lowest mortality rate was a combination of CMS, a carbapenem, and ampicillin-sulbactam. The colistin-susceptible and -resistant isolates from the same patients were highly related by PFGE, but isolates from different patients were not, suggesting evolution of resistance during CMS therapy. By MLST, all isolates belonged to the international clone II, the lineage that is epidemic worldwide. Phosphoethanolamine modification of lipid A was present in all colistin-resistant A. baumannii isolates.ConclusionsColistin-resistant A. baumannii occurred almost exclusively among patients who had received CMS for treatment of carbapenem-resistant, colistin-susceptible A. baumannii infection. Lipid A modification by the addition of phosphoethanolamine accounted for colistin resistance. Susceptibility testing for colistin should be considered for A. baumannii identified from CMS-experienced patients.

Project description:Even though colistin-based treatment represents the antimicrobial-regimen backbone for the management of multidrug-resistant Gram-negative infections, colistin resistance is still rare, at least as a full resistance, in Acinetobacter baumannii (Ab). We investigated the genomics and transcriptomics of two clinical Extensively Drug Resistance (XDR) colistin-susceptible/resistant (COL-S/R) Ab strain-pairs in which COL-resistance was developed after exposure to colistin therapy. The molecular characterization of the strains showed that all strains belonged to PFGE-A, ST-281, OXA-23 producers, Global Clone-II, and were resistant to imipenem, meropenem, ampicillin/sulbactam, ciprofloxacin, gentamicin, amikacin, trimethoprim/sulfamethoxazole, and susceptible to tigecycline, in agreement with NGS-acquired resistome. COL-R vs. COL-S Ab comparative genomics, mapping on Ab ATCC 17978 and Ab ACICU Reference Genomes, revealed a closely related genomic phylogeny, especially between strain-pair isolates, and distinctive common genomic non-synonymous SNPs (nsSNPs) in COL-R Ab strains. Furthermore, pmrB and pmrC nsSNPs were found. Notably we recovered, for the first time, lpxC and lpxD nsSNPs previously described only in "in-vitro" mutants and associated with colistin resistance in a clinical COL-R Ab. COL-R vs. COL-S Ab comparative transcriptomics evidenced a strain-dependent response to the colistin resistance onset highly variable among the single COL-R strains vs. their COL-S parents and merely seven common over-expressed transcripts, i.e. the PgaB lipoprotein for biofilm-matrix production, the diacylglycerol kinase for the lipid recycling in the membrane-derived oligosaccharide cycle, a membrane non-ribosomal peptide synthetase, the Lipid A phosphoethanol aminotransferase PmrC, and three hypothetical proteins. The transcript analysis of the "COL-R related genes" and the RNA-seq data confirmed pmrCAB over-expression responsible for a greater positive net cell-charge, and lpxACD under-expression in COL-R causing a decreased LPS production, as main mechanisms of colistin resistance. Our study reports the COL-R Ab genomic and transcriptomic signatures reflecting the interplay between several direct and indirect potential adaptations to antimicrobial pressure, including the occurrence of SNP accumulation hotspot loci in genes related to intrinsic or adaptive colistin resistance, surface adhesion proteins and porins, and over-expressed genes involved in different pathways, i.e. biofilm production, oxidative stress response, extensive drug and COL resistance.

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Constraint-based modeling identifies new putative targets to fight colistin-resistant A. baumannii infections.

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