Identification of synergists that potentiate the action of polymyxin B against Burkholderia cenocepacia

Loutet, Slade A.; El-Halfawy, Omar M.; Jassem, Agatha N; López, José María Sánchez; Medarde, Antonio Fernández; Speert, David P.; Davies, Julian; Valvano, Miguel A.

doi:10.1016/j.ijantimicag.2015.05.010

Cited by 4 publications

(5 citation statements)

References 28 publications

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“…In our assays, novobiocin had improved activity against B. cenocepacia at acidic pH. Loutet et al ( 44 ) showed synergy of novobiocin in combination with polymixin B and colistin against B. cenocepacia ( 44 ). Low MIC values for novobiocin have been reported against Burkholderia pseudomallei and Burkholderia mallei .…”

Section: Discussionsupporting

confidence: 53%

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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Section: Discussionsupporting

confidence: 53%

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

Morales,

Av-Gay,

Murphy

2023

Microbiol Spectr

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“…Checkerboard assays were conducted with combinations of antibiotics (obtained from Sigma, St Louis, MO, USA) as previously described [ 10 ]. Initial assays against B. cenocepacia K56–2 were conducted in LB medium to select the most potent combination.…”

Section: Methodsmentioning

confidence: 99%

“…These include three β-lactams (ceftazidime, meropenem, and ticarcillin-clavulanate), the fluoroquinolone levofloxacin, and trimethoprim-sulfamethoxazole combo (co-trimoxazole) in addition to the bacteriostatic drugs minocycline and chloramphenicol. New therapeutic solutions are being explored [ 10 – 12 ], but until they can be translated into clinical use, Bcc-infected patients are in dire need of effective therapeutics. We aimed to bridge this gap by finding novel combinations of clinically available antibiotics that could eradicate Bcc bacteria at physiologically relevant concentrations and could be readily used in patients.…”

Section: Introductionmentioning

confidence: 99%

Novel antibiotic combinations proposed for treatment of Burkholderia cepacia complex infections

El-Halfawy

Naguib

Valvano

2017

Antimicrob Resist Infect Control

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Effective strategies to manage Burkholderia cepacia complex (Bcc) infections in cystic fibrosis (CF) patients are lacking. We tested combinations of clinically available antibiotics and show that moxifloxacin-ceftazidime could inhibit 16 Bcc clinical isolates at physiologically achievable concentrations. Adding low dose of colistin improved the efficacy of the combo, especially at conditions mimicking CF respiratory secretions.

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“…The susceptibility of the strains to Polymyxin B was further examined by diluting overnight cultures 1:100 in LB and adding 270 μl to each well in duplicate in a 96‐well plate. A series of Polymyxin B concentrations, prepared in distilled water with 0.2% (w/v) BSA and 0.02% (v/v) acetic acid were serially diluted 1:10 to give a final concentration in the range of 16 to 1024 μg/ml and the plate incubated in a Biotek Synergy H1 Microplate reader at 37°C with medium shaking and OD 600nm measured every 15 min for 20 h (Loutet et al, 2015 ). Assessment of mucoid phenotype Exopolysaccharide (EPS) production was assessed to determine the mucoid phenotype of the mutant strains of Bcc using Yeast extract mannitol (YEM) (2 g/L Yeast extract, 20 g/L d ‐mannitol, 15 g/L Agar no.2) plates (Lagatolla et al, 2002 ).…”

Section: Table A1mentioning

confidence: 99%

Section: Table A1mentioning

confidence: 99%

A universal stress protein upregulated by hypoxia has a role in Burkholderia cenocepacia intramacrophage survival: Implications for chronic infection in cystic fibrosis

et al. 2022

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Universal stress proteins (USPs) are ubiquitously expressed in bacteria, archaea, and eukaryotes and play a lead role in adaptation to environmental conditions. They enable adaptation of bacterial pathogens to the conditions encountered in the human niche, including hypoxia, oxidative stress, osmotic stress, nutrient deficiency, or acid stress, thereby facilitating colonization. We previously reported that all six USP proteins encoded within a low‐oxygen activated ( lxa ) locus in Burkholderia cenocepacia showed increased abundance during chronic colonization of the cystic fibrosis (CF) lung. However, the role of USPs in chronic cystic fibrosis infection is not well understood. Structural modeling identified surface arginines on one lxa ‐encoded USP, USP76, which suggested it mediated interactions with heparan sulfate. Using mutants derived from the B. cenocepacia strain, K56‐2, we show that USP76 is involved in host cell attachment. Pretreatment of lung epithelial cells with heparanase reduced the binding of the wild‐type and complement strains but not the Δ usp76 mutant strain, indicating that USP76 is directly or indirectly involved in receptor recognition on the surface of epithelial cells. We also show that USP76 is required for growth and survival in many conditions associated with the CF lung, including acidic conditions and oxidative stress. Moreover, USP76 also has a role in survival in macrophages isolated from people with CF. Overall, while further elucidation of the exact mechanism(s) is required, we can conclude that USP76, which is upregulated during chronic infection, is involved in bacterial survival within CF macrophages, a hallmark of Burkholderia infection.

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Identification of synergists that potentiate the action of polymyxin B against Burkholderia cenocepacia

Cited by 4 publications

References 28 publications

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

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

Novel antibiotic combinations proposed for treatment of Burkholderia cepacia complex infections

A universal stress protein upregulated by hypoxia has a role in Burkholderia cenocepacia intramacrophage survival: Implications for chronic infection in cystic fibrosis

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