Raising the stakes: Loss of efflux-pump regulation decreases meropenem susceptibility in <i>Burkholderia pseudomallei</i>

Sarovich, Derek S.; Webb, Jessica R.; Pitman, Matthew C.; Viberg, Linda T.; Mayo, Mark; Baird, Robert W.; Robson, Jennifer; Currie, Bart J.; Price, Erin P.

doi:10.1101/205070

Cited by 9 publications

(31 citation statements)

References 49 publications

(68 reference statements)

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“…115 Furthermore, B. pseudomallei has the ability to develop decreased susceptibility toward meropenem during treatment (cases becoming refractory despite aggressive therapy), caused by multiple mutations and overexpression of multidrug resistance-nodulation-division efflux pumps. 116 In fact, blaOXA-57 gene (class D β-lactamase) carriage has been reported, but phenotypically isolates remain susceptible to imipenem. 117 Evidence for using novel agents such as ceftolozane-tazobactam in managing melioidosis has been shown in vitro, 118 but none yet replaced the role of ceftazidime.…”

Section: Clinical Managementmentioning

confidence: 99%

Melioidosis: A Neglected Cause of Community-Acquired Pneumonia

Virk

Mukhopadhyay

Wiersinga

2020

Semin Respir Crit Care Med

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AbstractMelioidosis, caused by the facultative intracellular gram-negative pathogen Burkholderia pseudomallei, is an emerging cause of community-acquired pneumonia across the tropics. The majority of patients present with pneumonia with or without sepsis, but localized and asymptomatic infection is also well recognized. Recent modeling and epidemiological studies have demonstrated the widespread presence of B. pseudomallei in otherwise unrecognized regions with a predicted mortality of 90,000 deaths worldwide. Innovative environmental studies are also uncovering how hydrodynamic, pedology, fauna, and weather events influence geographic distribution and incidence of melioidosis cases. Of concern is the changes associated with global warming, which will be conducive to B. pseudomallei in combination with the global diabetes pandemic. In fact, over 80% of patient developing melioidosis have underlying comorbidities. For this great mimicker, culture remains the mainstay of diagnosis and despite availability of other assays, challenges still remain in reducing time to diagnosis and avoiding misdiagnosis. With institution of timely antimicrobials such as ceftazidime and supportive intensive care, overall mortality can be reduced to 10%, although this can still be as high as 50% in poorly resourced areas. Promise is on the horizon with the first human vaccine trials being planned for 2021. Meanwhile new multiomics techniques are giving us a better understanding of the role of virulence and host–pathogen interactions on patient outcomes.

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Section: Clinical Managementmentioning

confidence: 99%

Melioidosis: A Neglected Cause of Community-Acquired Pneumonia

Virk

Mukhopadhyay

Wiersinga

2020

Semin Respir Crit Care Med

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“…Relapse of infection is common and is associated with increased mortality, particularly in cases were treatment is unsuccessful or an incomplete course of antimicrobial therapy is taken (10,11).…”

Section: Introductionmentioning

confidence: 99%

Peptidyl-Prolyl Isomerase ppiB Is Essential for Proteome Homeostasis and Virulence in Burkholderia pseudomallei

et al. 2019

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Burkholderia pseudomallei is the causative agent of melioidosis, a disease endemic to Southeast Asia and northern Australia. Mortality rates in these areas are high even with antimicrobial treatment, and there are few options for effective therapy. Therefore, there is a need to identify antibacterial targets for the development of novel treatments. Cyclophilins are a family of highly conserved enzymes important in multiple cellular processes. Cyclophilins catalyze the cis-trans isomerization of xaa-proline bonds, a rate-limiting step in protein folding which has been shown to be important for bacterial virulence. B. pseudomallei carries a putative cyclophilin B gene, ppiB, the role of which was investigated. A B. pseudomallei ΔppiB (BpsΔppiB) mutant strain demonstrates impaired biofilm formation and reduced motility. Macrophage invasion and survival assays showed that although the BpsΔppiB strain retained the ability to infect macrophages, it had reduced survival and lacked the ability to spread cell to cell, indicating ppiB is essential for B. pseudomallei virulence. This is reflected in the BALB/c mouse infection model, demonstrating the requirement of ppiB for in vivo disease dissemination and progression. Proteomic analysis demonstrates that the loss of PpiB leads to pleiotropic effects, supporting the role of PpiB in maintaining proteome homeostasis. The loss of PpiB leads to decreased abundance of multiple virulence determinants, including flagellar machinery and alterations in type VI secretion system proteins. In addition, the loss of ppiB leads to increased sensitivity toward multiple antibiotics, including meropenem and doxycycline, highlighting ppiB inhibition as a promising antivirulence target to both treat B. pseudomallei infections and increase antibiotic efficacy.

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“…Existing bioinformatic tools such as ARG-ANNOT [3], Antibiotic Resistance Identification By Assembly (ARIBA) [4], Comprehensive Antibiotic Resistance Database (CARD) [5], and MEGARes [2] can readily detect AMR genes acquired from horizontal gene transfer events. Many bacterial pathogens also develop AMR via chromosomal mutations, including missense single-nucleotide polymorphism (SNP) mutations in β -lactamase-encoding genes, SNPs or nonsense insertion-deletions (indels) in efflux pump regulators [6][7][8], gene amplification via copy-number variations (CNVs) [9], and functional gene loss [6]. Recent improvements in AMR identification software mean that chromosomal mutations, particularly SNPs, are now identifiable.…”

Section: Introductionmentioning

confidence: 99%

“…As such, isolates collected prior to antibiotic treatment are almost universally susceptible to the following clinically-relevant antibiotics: ceftazidime (CAZ), amoxicillin-clavulanate (AMC), co-trimoxazole (SXT), doxycycline (DOX), meropenem (MEM) and imipenem (IPM) [13]. To prevent melioidosis relapse, treatment involves prolonged (3-6 month) antibiotic therapy, which increases AMR risk and treatment failure [6]. AMR in B. pseudomallei has been reported for all clinically-relevant antibiotics [6], with novel AMR determinants towards these key antibiotics continuing to be uncovered.…”

Section: Introductionmentioning

confidence: 99%

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Taking the next-gen step: comprehensive antimicrobial resistance detection from Burkholderia pseudomallei genomes

Madden

Webb

Steinig

et al. 2019

Preprint

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Antimicrobial resistance (AMR) is emerging as a major threat to human health worldwide. Whole-genome sequencing (WGS) holds great potential for rapidly and accurately detecting AMR from genomic data in the diagnostic laboratory setting. However, most work to date has focussed on identifying only horizontally-acquired AMRconferring genes, with chromosomally-encoded AMR determinants remaining largely undetected. Here, we present an improved tool for Antibiotic Resistance Detection and Prediction (ARDaP) from WGS data. ARDaP was designed with three priorities: 1) to accurately identify a wide range of AMR genetic determinants (i.e. horizontallyacquired gene gain, single-nucleotide polymorphisms, insertionsdeletions, copy-number variation, and functional gene loss); 2) to predict enigmatic AMR determinants based on novel mutants with moderate-or high-consequence impacts in known AMR-conferring genes, and 3) to detect minor AMR allelic determinants in mixed (e.g. metagenomic) sequence data. ARDaP performance was demonstrated in the melioidosis pathogen, Burkholderia pseudomallei, due to its exclusively chromosomally-encoded AMR determinants and inherently limited treatment options. Using a well-characterised collection of 1,063 clinical strains, ARDaP accurately detected all currently known AMR determinants in B. pseudomallei (~50 determinants), including stepwise AMR mutations. Additionally, ARDaP accurately predicted meropenem resistance in four previously uncharacterised B. pseudomallei isolates. In mixed strain data, ARDaP identified AMR determinants down to~5% allelic frequency, enabling the early detection of emerging AMR. We demonstrate that ARDaP is an accurate tool for identifying and predicting all confirmed B. pseudomallei AMR determinants from WGS data, including from mixed strain data. Finally, our study illustrates that manual cataloguing and functional verification of putative AMR determinants in individual pathogens is essential for truly comprehensive AMR detection. ARDaP is open source and available at: github.com/dsarov/ARDaP

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Raising the stakes: Loss of efflux-pump regulation decreases meropenem susceptibility in Burkholderia pseudomallei

Cited by 9 publications

References 49 publications

Melioidosis: A Neglected Cause of Community-Acquired Pneumonia

Melioidosis: A Neglected Cause of Community-Acquired Pneumonia

Peptidyl-Prolyl Isomerase ppiB Is Essential for Proteome Homeostasis and Virulence in Burkholderia pseudomallei

Taking the next-gen step: comprehensive antimicrobial resistance detection from Burkholderia pseudomallei genomes

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