Revisiting aminocoumarins for the treatment of melioidosis

Willcocks, Sam; Cia, Felipe; Francisco, Amanda Fortes; Wren, Brendan W.

doi:10.1016/j.ijantimicag.2020.106002

Cited by 7 publications

(5 citation statements)

References 26 publications

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“…These in vivo studies were initiated as an extension of our earlier in vitro studies with five bacterial biothreat agents [ 8 ]. The animal investigations with B. pseudomallei also expanded upon those described by Willcocks et al [ 9 ]. In the latter, Novo and other aminocoumerins were evaluated for in vivo potency against B. pseudomallei .…”

Section: Discussionmentioning

confidence: 82%

“…The objective of our research was to repurpose and evaluate the antimicrobial agent novobiocin (Novo), an aminocoumarin class antibiotic, as a novel therapeutic approach to counteract natural or engineered resistance to conventional antibiotics, promote more complete and rapid clearance of infection, and increase survival of mice exposed to a lethal infection with the bacterial threat agents of melioidosis and anthrax. Novo is a potent bactericidal antibiotic having broad in vitro efficacy against several high consequence pathogens [ 7 , 8 , 9 ]. It is a licensed but under-utilized early-generation antibiotic which exhibits low effective concentrations against highly disparate agents such as Francisella tularensis , the pathogenic Burkholderia spp., and Bacillus anthracis [ 8 , 9 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…Novo is a potent bactericidal antibiotic having broad in vitro efficacy against several high consequence pathogens [ 7 , 8 , 9 ]. It is a licensed but under-utilized early-generation antibiotic which exhibits low effective concentrations against highly disparate agents such as Francisella tularensis , the pathogenic Burkholderia spp., and Bacillus anthracis [ 8 , 9 , 10 , 11 , 12 ]. The minimum inhibitory concentration (MIC) of Novo for B. anthracis and B. pseudomallei were determined to be 0.82 (range 0.49–1.95) µg/ mL and 1.63 (range 0.98–1.95) µg/mL respectively [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of Treatment with the Antibiotic Novobiocin against Infection with Bacillus anthracis or Burkholderia pseudomallei

et al. 2022

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The microbial pathogens Burkholderia pseudomallei and Bacillus anthracis are unrelated bacteria, yet both are the etiologic agents of naturally occurring diseases in animals and humans and are classified as Tier 1 potential biothreat agents. B. pseudomallei is the Gram-negative bacterial agent of melioidosis, a major cause of sepsis and mortality globally in endemic tropical and subtropical regions. B. anthracis is the Gram-positive spore-forming bacterium that causes anthrax. Infections acquired by inhalation of these pathogens are challenging to detect early while the prognosis is best; and they possess innate multiple antibiotic resistance or are amenable to engineered resistance. Previous studies showed that the early generation, rarely used aminocoumarin novobiocin was very effective in vitro against a range of highly disparate biothreat agents. The objective of the current research was to begin to characterize the therapeutic efficacy of novobiocin in mouse models of anthrax and melioidosis. The antibiotic was highly efficacious against infections by both pathogens, especially B. pseudomallei. Our results supported the concept that specific older generation antimicrobials can be effective countermeasures against infection by bacterial biothreat agents. Finally, novobiocin was shown to be a potential candidate for inclusion in a combined pre-exposure vaccination and post-exposure treatment strategy designed to target bacterial pathogens refractory to a single medical countermeasure.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficacy of Treatment with the Antibiotic Novobiocin against Infection with Bacillus anthracis or Burkholderia pseudomallei

et al. 2022

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“…Coumermycin was also shown to be effective against Burkholderia species and to have superior properties than novobiocin. Willcocks et al ( 49 ) found that coumermycin has increased activity against B. pseudomallei in G. mellonella larvae compared to novobiocin and protected against acute melioidosis in a murine infection model ( 49 ). They attributed increased protection to a longer half-life in plasma compared to novobiocin.…”

Section: Discussionmentioning

confidence: 99%

Acidic pH modulates Burkholderia cenocepacia antimicrobial susceptibility in the cystic fibrosis nutritional environment

Morales,

Av-Gay,

Murphy

2023

Microbiol Spectr

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Burkholderia cenocepacia is an opportunistic pathogen correlated with increased disease severity and mortality in cystic fibrosis (CF) patients. One major difficulty when treating these infections in CF is the poor relationship between in vitro susceptibility and clinical outcome. Previous analysis of CF sputum samples showed elevated levels of zinc and iron ions and an acidic pH (2.9–6.5) compared to healthy individuals. Additionally, B. cenocepacia grows at an acidic pH (~3.5) in vitro and persists for 24 h in the intracellular acid compartments of amoebas and macrophages. We seek to understand the impact of acidic pH and increased zinc and iron concentrations on antibiotic susceptibility in the CF nutritional environment. The Synthetic Cystic Fibrosis sputum Media (SCFM) was modified to represent the acidic pH and increased zinc and iron concentrations found in CF sputum (SCFM-FeZn). We found that the nutritional environment modulated B. cenocepacia susceptibility to antimicrobials, and more strikingly, acidic pH decreased susceptibility to most antimicrobials used clinically to treat these infections. Finally, we assessed susceptibility against a custom compound library of antimicrobials using SCFM-FeZn agar plates. Out of 591 antibiotics, only 18 were active against B. cenocepacia at both neutral and acidic pH. Four of these compounds (novobiocin, coumermycin, mitomycin C, and streptonigrin) were selected for susceptibility assays in liquid culture. Here, we show that acidic pH modulates antimicrobial susceptibility in the CF nutritional environment and that susceptibility testing in media that mimic the host nutritional environment could pave the way to finding new therapies against infections in CF. IMPORTANCE Burkholderia cenocepacia causes severe infections in cystic fibrosis (CF) patients. CF patients are prone to reoccurring infections due to the accumulation of mucus in their lungs, where bacteria can adhere and grow. Some of the antibiotics that inhibit B. cenocepacia in the laboratory are not effective for CF patients. A major contributor to poor clinical outcomes is that antibiotic testing in laboratories occurs under conditions that are different from those of sputum. CF sputum may be acidic and have increased concentrations of iron and zinc. Here, we used a medium that mimics CF sputum and found that acidic pH decreased the activity of many of the antibiotics used against B. cenocepacia . In addition, we assessed susceptibility to more than 500 antibiotics and found four active compounds against B. cenocepacia . Our findings give a better understanding of the lack of a relationship between susceptibility testing and the clinical outcome when treating B. cenocepacia infections.

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“…Burkholderia pseudomallei (BP) is a gram-negative, environmental saprophyte predominately found in the soil and surface groundwater of endemic tropical and subtropical regions worldwide [ 1 , 2 ]. BP is the etiological agent of melioidosis, a life-threatening disease that accounts for approximately 89,000 deaths per year worldwide [ 2 - 6 ]. Diabetes mellitus remains a major risk factor for melioidosis; therefore, the rising global diabetes pandemic could further escalate the number of deaths attributed to melioidosis [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Biofilm Signaling, Composition and Regulation in Burkholderia pseudomallei

Nyanasegran

Nathan

Firdaus-Raih

et al. 2022

J. Microbiol. Biotechnol.

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The incidence of melioidosis cases caused by the gram-negative pathogen Burkholderia pseudomallei (BP) is seeing an increasing trend that has spread beyond its previously known endemic regions. Biofilms produced by BP have been associated with antimicrobial therapy limitation and relapse melioidosis, thus making it urgently necessary to understand the mechanisms of biofilm formation and their role in BP biology. Microbial cells aggregate and enclose within a self-produced matrix of extracellular polymeric substances (EPSs) to form biofilm. The transition mechanism of bacterial cells from planktonic state to initiate biofilm formation, which involves the formation of surface attachment microcolonies and the maturation of the biofilm matrix, is a dynamic and complex process. Despite the emerging findings on the biofilm formation process, systemic knowledge on the molecular mechanisms of biofilm formation in BP remains fractured. This review provides insights into the signaling systems, matrix composition, and the biosynthesis regulation of EPSs (exopolysaccharide, eDNA and proteins) that facilitate the formation of biofilms in order to present an overview of our current knowledge and the questions that remain regarding BP biofilms.

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Revisiting aminocoumarins for the treatment of melioidosis

Abstract: Highlights Aminocoumarins can be used to treat acute pulmonary melioidosis in a murine model. Formulation with l -tyrosine or dl -tryptophan enhances the bioactivity of aminocoumarins. Utility of Galleria mellonella larvae for in vivo drug efficacy screening.

Cited by 7 publications

References 26 publications

Efficacy of Treatment with the Antibiotic Novobiocin against Infection with Bacillus anthracis or Burkholderia pseudomallei

Efficacy of Treatment with the Antibiotic Novobiocin against Infection with Bacillus anthracis or Burkholderia pseudomallei

Acidic pH modulates Burkholderia cenocepacia antimicrobial susceptibility in the cystic fibrosis nutritional environment

Biofilm Signaling, Composition and Regulation in Burkholderia pseudomallei

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