Biology subjects

Bonomo, R. A.

Publications and source records attributed to Bonomo, R. A..

4 recordsLinked to original sources

bioRxiv2018

The Clinical and Molecular Epidemiology of CTX-M-9 Group Producing Enterobacteriaceae infections in children

BackgroundThe pandemic of extended-spectrum-beta-lactamase (ESBL)-producing-Enterobacteriaceae (Ent) is strongly linked to the dissemination of CTX-M-type-ESBL-Ent. We sought to define the epidemiology of infections in children due to an emerging resistance type, CTX-M-9-group-producing-Ent (CTX-M-9-grp-Ent).\n\nMethodsA multi-centered case-control analysis of Chicago children with CTX-M-9-grp-Ent infections was performed. Cases were defined as children possessing extended-spectrum-cephalosporin-resistant (ESC-R) infections. PCR and DNA analysis assessed beta-lactamase (bla) genes, multi-locus sequence types (MLST) and phylogenetic grouping of E. coli. Controls were children with ESC-susceptible (ESC-S)-Ent infections matched 3:1 by age, source, and hospital. The clinical-epidemiologic predictors of CTX-M-9-grp-Ent infection were assessed.\n\nResultsOf 356 ESC-R-Ent isolates from children (median age 4.1 years), CTX-M-9-group was the solely detected bla gene in 44(12.4%). The predominant species was E. coli (91%) of virulent phylogroups D(60%) and B2(40%). MLST revealed multiple strain types. On multivariable analysis, CTX-M-9-grp-Ent occurred more often in E. coli (OR 7.0), children of non-black-white-Hispanic race (OR 6.5), and outpatients (OR 4.5) which was a very unexpected finding for infections due to antibiotic-resistant bacteria. Residents of South Chicago were 6.7 times more likely to have CTX-M-9-grp-Ent infections than those in the reference region (West), while residence in Northwestern Chicago was associated with an 81% decreased risk. Other demographic, comorbidity, invasive-device, and antibiotic use differences were not found.\n\nConclusionsCTX-M-9-grp-Ent infection is strikingly associated with patient residence and is occurring in children without traditional in-patient exposure risk factors. This suggests that among children, the community environment may be a key contributor in the spread of these resistant pathogens.

epidemiology↗

bioRxiv2018

A non-canonical metal center drives activity of the Sediminispirochaeta smaragdinae metallo-β- lactamase SPS-1

In an effort to evaluate whether a recently reported putative metallo-{beta}-lactamase (M{beta}L) contains a novel M{beta}L active site, SPS-1 from Sediminispirochaeta smaragdinae was over-expressed, purified, and characterized using spectroscopic and crystallographic studies. Metal analyses demonstrate that recombinant SPS-1 binds nearly 2 equivalents of Zn (II), and steady-state kinetic studies show that the enzyme hydrolyzes carbapenems and certain cephalosporins but not {beta}-lactam substrates with bulky substituents in the 6-7 position. Spectroscopic studies on Co (II)-substituted SPS-1 suggest a novel metal center in SPS-1, with reduced spin coupling between the metal ions and a novel Zn1 metal binding site. This site was confirmed with a crystal structure of the enzyme. The structure shows a Zn2 site that is similar that that in NDM-1 and other subclass B1 M{beta}Ls; however, the Zn1 metal ion is coordinated by 2 histidine residues and a water molecule, which is held in position by a hydrogen bond network. The Zn1 metal is displaced nearly 1 [A] from the position reported in other M{beta}Ls. The structure also shows extended helices above the active site, which create a binding pocket that precludes the binding of substrates with large, bulky substituents in the 6/7 position of {beta}-lactam antibiotics. This study reveals a novel metal binding site in M{beta}Ls, and suggests that the targeting of metal binding sites in M{beta}Ls with inhibitors is now more challenging with the identification of this new M{beta}L.

biochemistry↗

bioRxiv2018

Interspecies DNA acquisition by a naturally competent Acinetobacter baumannii strain

Acinetobacter baumannii is a human pathogen that frequently acquires antibiotic resistance genes leading to the emergence of multi-drug-resistant (MDR) strains. To investigate the role of transformation in the acquisition of resistance determinants by this species, the susceptible strain A118 was exposed to genomic DNA of carbapenem-resistant Klebsiella pneumoniae (CRKp). Resistant transformants were obtained and an increase in the resistance level to all {beta}-lactam antibiotics was observed. Whole genome analysis of transformant clones demonstrated the acquisition of CRKp DNA. The most frequently acquired genes correspond to mobile elements, antibiotic resistance genes, and operons involved in metabolism. Bioinformatic analyses and in silico gene flow prediction strengthen our findings, showing that a continuing exchange of genetic material between A. baumannii and K. pneumoniae occurs when they share the same niche. Our results reinforce the idea that natural transformation may play a key role in the increasing emergence of A. baumannii MDR.\n\nIMPORTANCESince the characterization of antibiotic resistance in the late 50s, antibiotic resistance propagation was classically associated with horizontal gene transfer (HGT) mediated by plasmids bearing multiple resistance genes. Here we show that, at least in the human pathogen A. baumannii, transformation also plays a major role in the acquisition of antibiotic resistance determinants. This study unravels that at least for certain pathogens the propagation of resistance genes occurs by alternative HGT mechanisms which in the past have been unappreciated.

microbiology↗

bioRxiv2018

Community origins and regional differences in plasmid-mediated fluoroquinolone resistant Enterobacteriaceae infections in children

BackgroundFluoroquinolones (FQs) are uncommonly prescribed in children, yet pediatric multidrug-resistant (MDR)-Enterobacteriaceae (Ent) infections often reveal FQ resistance (FQR). We sought to define the molecular epidemiology of FQR and MDR-Ent in children.\n\nMethodsA case-control analysis of children with MDR-Ent infections at 3 Chicago hospitals was performed. Cases were children with third-generation-cephalosporin-resistant (3GCR) and/or carbapenem-resistant (CR)-Ent infections. PCR and DNA analysis assessed bla and plasmid-mediated FQR (PMFQR) genes. Controls were children with 3GC and carbapenem susceptible-Ent infections matched by age, source and hospital. We assessed clinical-epidemiologic predictors of PMFQR Ent infection.\n\nResultsOf 169 3GCR and/or CR Ent isolates from children (median age 4.8 years), 85 were FQR; 56 (66%) contained PMFQR genes. The predominant organism was E. coli and most common bla gene bla CTX-M-1 group. In FQR isolates, PMFQR gene mutations included aac61b-cr, oqxA/B, qepA, and qnrA/B/D/S in 83%, 15%, 13% and 11% of isolates, respectively. FQR E. coli was often associated with phylogroup B2, ST43/ST131. On multivariable analysis, PMFQR Ent infections occurred mostly in outpatients (OR 33.1) of non-black-white-Hispanic race (OR 6.5). Residents of Southwest Chicago were >5 times more likely to have PMFQR-Ent infections than those in the reference region, while residence in Central Chicago was associated with a 97% decreased risk. Other demographic, comorbidity, invasive-device, antibiotic use, or healthcare differences were not found.\n\nConclusionsThe strong association of infection with MDROs showing FQR with patient residence rather than with traditional risk factors suggests that the community environment is a major contributor to spread of these pathogens in children.

epidemiology↗