Novel transferable<i>erm</i>(46) determinant responsible for emerging macrolide resistance in<i>Rhodococcus equi</i>

Anastasi, Elisa; Giguère, Steeve; Berghaus, Londa J.; Hondalus, Mary K.; Willingham-Lane, Jennifer M.; MacArthur, Iain; Cohen, Noah D.; Roberts, Marilyn C.; Vázquez‐Boland, José A.

doi:10.1093/jac/dkv279

Cited by 32 publications

(53 citation statements)

References 41 publications

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“…Additionally, while the specific location of the ICE erm(46) in R. equi is not described, it could be housed within a transposon that also possesses unknown genes influencing bacterial fitness under different environmental conditions. Our laboratory previously demonstrated that the erm(46) gene is transferrable to susceptible R. equi isolates, providing macrolide resistance (12). If the ICE erm(46) gene is transferrable to other bacterial species, R. equi could serve as an environmental reservoir for macrolide resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Mating was performed as described by Tripathi et al (37). R. equi strain 103S erm(46) Zeo r , possessing the mobile element erm(46) and chromosomally marked with the Streptoalloteichus hindustanus ble gene (conferring resistance to zeocin), was used as the donor (38). For transfer of erm(46), equal numbers of six recipient R. equi isolates (isolates 1, 1R, 2, 2R, 3, or 3R) and the zeocin-marked donor strain were used ( Table 2).…”

Section: Methodsmentioning

confidence: 99%

“…To date, four single base pair mutations in the rpoB gene have been described (11). Macrolide resistance in R. equi, in contrast, is conferred by acquisition of an integrative conjugative element (ICE) carrying a new rRNA methylation gene, designated erm(46) (12).…”

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Effect of Macrolide and Rifampin Resistance on the Fitness of Rhodococcus equi

Willingham-Lane

Berghaus

et al. 2019

Appl Environ Microbiol

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Rhodococcus equi is a leading cause of severe pneumonia in foals. Standard treatment is dual antimicrobial therapy with a macrolide and rifampin, but the emergence of macrolide- and rifampin-resistant R. equi isolates is an increasing problem. The objective of this study was to determine the effect of macrolide and/or rifampin resistance on fitness of R. equi. Three unique isogenic sets were created, each consisting of four R. equi strains, as follows: a susceptible parent isolate, strains resistant to macrolides or rifampin, and a dual macrolide- and rifampin-resistant strain. Each isogenic set’s bacterial growth curve was generated in enriched medium, minimal medium (MM), and minimal medium without iron (MM-I). Bacterial survival in soil was analyzed over 12 months at −20°C, 4°C, 25°C, and 37°C, and the ability of these strains to retain antimicrobial resistance during sequential subculturing was determined. Insertion of the mobile element conferring macrolide resistance had minimal effect on in vitro growth. However, two of three rpoB mutations conferring rifampin resistance resulted in a decreased growth rate in MM. In soil, macrolide- or rifampin-resistant R. equi strains exhibited limited growth compared to that of the susceptible R. equi isolate at all temperatures except −20°C. During subculturing, macrolide resistance was lost over time, and two of three rpoB mutations reverted to the wild-type form. The growth of rifampin-resistant R. equi colonies is delayed under nutrient restriction. In soil, possession of rifampin or macrolide resistance results in decreased fitness. Both macrolide and rifampin resistance can be lost after repeated subculturing. IMPORTANCE This work advances our understanding of the opportunistic environmental pathogen Rhodococcus equi, a disease agent affecting horses and immunocompromised people. R. equi is one of the most common causes of severe pneumonia in young horses. For decades, the standard treatment for R. equi pneumonia in horses has been dual antimicrobial therapy with a macrolide and rifampin; effective alternatives to this combination are lacking. The World Health Organization classifies these antimicrobial agents as critically important for human medicine. Widespread macrolide and rifampin resistance in R. equi isolates is a major emerging problem for the horse-breeding industry and might also adversely impact human health if resistant strains infect people or transfer resistance mechanisms to other pathogens. This study details the impact of antimicrobial resistance on R. equi fitness, a vital step for understanding the ecology and epidemiology of resistant R. equi isolates, and will support development of novel strategies to combat antimicrobial resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Effect of Macrolide and Rifampin Resistance on the Fitness of Rhodococcus equi

Willingham-Lane

Berghaus

et al. 2019

Appl Environ Microbiol

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“…Shotgun 101-bp pair-end DNA sequencing was performed at Beijing Genomics Institute (BGI, China) using TruSeq DNA PCR-Free Sample library preparation kit on Illumina HiSeq 2000 instruments. Strains 2274 to 2288 (supplementary table S1, Supplementary Material online) were sequenced at the genomics facility of the University of Georgia (USA) as previously described (Anastasi et al 2015). Adaptors and low quality reads were trimmed using Scythe (https://github.com/vsbuffalo/scythe) and Sickle (https://github.com/najoshi/sickle), respectively, and assembled using SPAdes (Bankevich et al 2012).…”

Section: Methodsmentioning

confidence: 99%

Pangenome and Phylogenomic Analysis of the Pathogenic ActinobacteriumRhodococcus equi

et al. 2016

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We report a comparative study of 29 representative genomes of the animal pathogen Rhodococcus equi. The analyses showed that R. equi is genetically homogeneous and clonal, with a large core genome accounting for ≈80% of an isolates’ gene content. An open pangenome, even distribution of accessory genes among the isolates, and absence of significant core–genome recombination, indicated that gene gain/loss is a main driver of R. equi genome evolution. Traits previously predicted to be important in R. equi physiology, virulence and niche adaptation were part of the core genome. This included the lack of a phosphoenolpyruvate:carbohydrate transport system (PTS), unique among the rhodococci except for the closely related Rhodococcus defluvii, reflecting selective PTS gene loss in the R. equi–R. defluvii sublineage. Thought to be asaccharolytic, rbsCB and glcP non-PTS sugar permease homologues were identified in the core genome and, albeit inefficiently, R. equi utilized their putative substrates, ribose and (irregularly) glucose. There was no correlation between R. equi whole-genome phylogeny and host or geographical source, with evidence of global spread of genomovars. The distribution of host-associated virulence plasmid types was consistent with the exchange of the plasmids (and corresponding host shifts) across the R. equi population, and human infection being zoonotically acquired. Phylogenomic analyses demonstrated that R. equi occupies a central position in the Rhodococcus phylogeny, not supporting the recently proposed transfer of the species to a new genus.

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“…Minocycline and doxycycline may be useful alternatives to currently used antimicrobial agents owing to their accumulation in lung tissue as well as their in vitro activity against many bacterial species commonly isolated from foals with pneumonia (Bryant et al, 2000;Jacks et al, 2003;Schnabel et al, 2012). In addition, tetracyclines are active against isolates of R. equi that are resistant to macrolides and rifampin (Gigu ere et al, 2010;Anastasi et al, 2015). Doxycycline has been investigated for the treatment of bacterial bronchopneumonia in foals (Venner et al, 2013) and proposed as an alternative treatment for foals infected with isolates of R. equi that are resistant to macrolides (Gigu ere et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Comparative pharmacokinetics of minocycline in foals and adult horses

Giguère

Burton

Berghaus

et al. 2016

Vet Pharm & Therapeutics

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The objective of this study was to compare the pharmacokinetics of minocycline in foals vs. adult horses. Minocycline was administered to six healthy 6- to 9-week-old foals and six adult horses at a dose of 4 mg/kg intragastrically (IG) and 2 mg/kg intravenously (i.v.) in a cross-over design. Five additional oral doses were administered at 12-h intervals in foals. A microbiologic assay was used to measure minocycline concentration in plasma, urine, synovial fluid, and cerebrospinal fluid (CSF). Liquid chromatography-tandem mass spectrometry was used to measure minocycline concentrations in pulmonary epithelial lining fluid (PELF) and bronchoalveolar (BAL) cells. After i.v. administration to foals, minocycline had a mean (±SD) elimination half-life of 8.5 ± 2.1 h, a systemic clearance of 113.3 ± 26.1 mL/h/kg, and an apparent volume of distribution of 1.24 ± 0.19 L/kg. Pharmacokinetic variables determined after i.v. administration to adult horses were not significantly different from those determined in foals. Bioavailability was significantly higher in foals (57.8 ± 19.3%) than in adult horses (32.0 ± 18.0%). Minocycline concentrations in PELF were higher than in other body fluids. Oral minocycline dosed at 4 mg/kg every 12 h might be adequate for the treatment of susceptible bacterial infections in foals.

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Novel transferableerm(46) determinant responsible for emerging macrolide resistance inRhodococcus equi

Abstract: This is the first molecular characterization of resistance to macrolides, lincosamides and streptogramins B in R. equi. Resistance was due to the presence of a novel erm(46) gene mobilizable likely by conjugation, which has spread among equine isolates of R. equi in the USA.

Cited by 32 publications

References 41 publications

Effect of Macrolide and Rifampin Resistance on the Fitness of Rhodococcus equi

Effect of Macrolide and Rifampin Resistance on the Fitness of Rhodococcus equi

Pangenome and Phylogenomic Analysis of the Pathogenic ActinobacteriumRhodococcus equi

Comparative pharmacokinetics of minocycline in foals and adult horses

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