Finafloxacin overcomes<i>Burkholderia pseudomallei</i>efflux-mediated fluoroquinolone resistance

Randall, Linnell B.; Georgi, Enrico; Genzel, Gelimer H.; Schweizer, Herbert P.

doi:10.1093/jac/dkw529

Cited by 15 publications

(16 citation statements)

References 10 publications

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“…The probability of any one gene being mutated seven times given our dataset is 1.65x10 -23 . Homologs of this locus in other Burkholderia species are annotated as bpeT , which is strongly associated with drug resistance [34–36]. A locus with five multiple mutations (P = 6.48x10 -16 ) encodes N-acetylmuramoyl-L-alanine amidase (AmpD, BMUL_2790), which is associated with resistance to β-lactam antibiotics [30].…”

Section: Resultsmentioning

confidence: 99%

A genome-wide association analysis reveals a potential role for recombination in the evolution of antimicrobial resistance in Burkholderia multivorans

et al. 2018

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Cystic fibrosis (CF) lung infections caused by members of the Burkholderia cepacia complex, such as Burkholderia multivorans, are associated with high rates of mortality and morbidity. We performed a population genomics study of 111 B. multivorans sputum isolates from one CF patient through three stages of infection including an early incident isolate, deep sampling of a one-year period of chronic infection occurring weeks before a lung transplant, and deep sampling of a post-transplant infection. We reconstructed the evolutionary history of the population and used a lineage-controlled genome-wide association study (GWAS) approach to identify genetic variants associated with antibiotic resistance. We found the incident isolate was basally related to the rest of the strains and more susceptible to antibiotics from three classes (β-lactams, aminoglycosides, quinolones). The chronic infection isolates diversified into multiple, distinct genetic lineages and showed reduced antimicrobial susceptibility to the same antibiotics. The post-transplant reinfection isolates derived from the same source as the incident isolate and were genetically distinct from the chronic isolates. They also had a level of susceptibility in between that of the incident and chronic isolates. We identified numerous examples of potential parallel pathoadaptation, in which multiple mutations were found in the same locus or even codon. The set of parallel pathoadaptive loci was enriched for functions associated with virulence and resistance. Our GWAS analysis identified statistical associations between a polymorphism in the ampD locus with resistance to β-lactams, and polymorphisms in an araC transcriptional regulator and an outer membrane porin with resistance to both aminoglycosides and quinolones. Additionally, these three loci were independently mutated four, three and two times, respectively, providing further support for parallel pathoadaptation. Finally, we identified a minimum of 14 recombination events, and observed that loci carrying putative parallel pathoadaptations and polymorphisms statistically associated with β-lactam resistance were over-represented in these recombinogenic regions.

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Section: Resultsmentioning

confidence: 99%

A genome-wide association analysis reveals a potential role for recombination in the evolution of antimicrobial resistance in Burkholderia multivorans

et al. 2018

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“…Recently, we have shown that the oral formulation of finafloxacin has utility in treating infection with the biothreat agent Burkholderia pseudomallei in a BALB/c mouse model of melioidosis (Barnes et al, 2017). It has been suggested that this superior efficacy at infection-relevant pH (in addition to its activity at neutral pH) is due to ability to maintain activity and not be affected by eﬄux (Randall et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

The Fluoroquinolone Finafloxacin Protects BALB/c Mice Against an Intranasal Infection With Francisella tularensis Strain SchuS4

et al. 2019

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The efficacy of the novel fluoroquinolone finafloxacin was evaluated as a potential therapeutic in vitro and in vivo , following an intranasal infection of Francisella tularensis strain SchuS4 in BALB/c mice. We demonstrated that short treatment courses of finafloxacin provide high levels of protection, with a single dose resulting in a significant increase in time to death when compared to ciprofloxacin. In addition, following investigation into the window of opportunity for treatment, we have shown that finafloxacin can provided protection when administered up to 96 h post-challenge. This is particularly encouraging since mice displayed severe signs of disease at this time point. In summary, finafloxacin may be a promising therapy for use in the event of exposure to F. tularensis , perhaps enabling the treatment regimen to be shortened or if therapy is delayed. The efficacy of finafloxacin against other biological threat agents also warrants investigation.

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“…Doxycycline and ciprofloxacin were used as control antibiotics, as they are prone to efflux, particularly by the BpeEF-OprC pump in B. pseudomallei (41, 48). The observed MIC for GC-072 against B.…”

Section: Resultsmentioning

confidence: 99%

“…Bp320 is a Δ( bpeEF-oprC ) derivative of Δ( amrAB-oprA ) Δ( bpeAB-oprB ) strain Bp282 and was constructed using the previously described methods. This strain does not express any known efflux pumps (48). bThe MIC against each strain was determined using broth microdilution assays.…”

Section: Resultsmentioning

confidence: 99%

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GC-072, a Novel Therapeutic Candidate for Oral Treatment of Melioidosis and Infections Caused by Select Biothreat Pathogens

Shearer

Saylor

Butler

et al. 2019

Antimicrob Agents Chemother

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Burkholderia pseudomallei, the etiological agent of melioidosis, is a Gram-negative bacterium with additional concern as a biothreat pathogen. The mortality rate from B. pseudomallei varies depending on the type of infection and extent of available health care; in the case of septicemia, left untreated, it can range from 50% to 90%. Current therapy for melioidosis is biphasic, consisting of parenteral acute-phase treatment for 2 weeks or longer, followed by oral eradication-phase treatment lasting several months.

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Finafloxacin overcomesBurkholderia pseudomalleiefflux-mediated fluoroquinolone resistance

Cited by 15 publications

References 10 publications

A genome-wide association analysis reveals a potential role for recombination in the evolution of antimicrobial resistance in Burkholderia multivorans

A genome-wide association analysis reveals a potential role for recombination in the evolution of antimicrobial resistance in Burkholderia multivorans

The Fluoroquinolone Finafloxacin Protects BALB/c Mice Against an Intranasal Infection With Francisella tularensis Strain SchuS4

GC-072, a Novel Therapeutic Candidate for Oral Treatment of Melioidosis and Infections Caused by Select Biothreat Pathogens

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