Enhancement of Burkholderia cepacia antimicrobial susceptibility by cationic compounds

Abstract

Infections in cystic fibrosis (CF) due to Burkholderia cepacia are challenging due to their resistance to antibiotics. We explored a new strategy for increasing the permeability of B. cepacia using cationic agents, including amino compounds, to reduce the MICs of standard antibiotics. Twenty-eight B. cepacia isolates from four CF centres in North America and four non-CF B. cepacia were examined by standard microtitre broth dilution methods for susceptibility to a variety of antibiotics in the presence of non-inhibitory concentrations of diaminoacetone (DAA), methylglyoxal bis-guanylhydrazone (MGBH), chlorpromazine (CPZ) and prochlorperazine (PCPZ). The proportion of isolates with greater than four-fold reductions in MIC in the presence of 0.3 mM CPZ or 0.4 mM PCPZ were 90% and 94% for gentamicin, 80% and 83% for tobramycin, 45% and 17% for ceftazidime, and 35% and 17% for amifloxacin. CPZ showed the same degree of reduction in the MIC of azithromycin in 79% strains (MIC50 reduced to 16 from > or = 256 mg/L). Non-CF B. cepacia showed a greater than four-fold reduction in MIC with CPZ for gentamicin, tobramycin and azithromycin and two-fold reduction for ceftazidime. Little or no reduction in MIC was seen with DAA or MGBH for any antibiotic. Addition of magnesium ions to the medium competitively inhibited any MIC reduction effect seen with the cationic agents. CPZ and PCPZ appeared to enhance the permeability of B. cepacia to antibiotics based upon ionic charge characteristics of the antibiotic. No significant differences were seen in outer membrane protein and lipopolysaccharide profiles between the culture treated with CPZ and the respective control culture of strain B. cepacia ATCC 13945. The fluorescent probe 1N-phenylnaphthylamine had no increased access across the outer membrane in the presence of CPZ for B. cepacia ATCC 13945. However, thin-section electron microscopy revealed separation between the outer membrane and the rest of the cytoplasm accompanied by a widening of the periplasmic space. These data provide a rationale for investigating amino compounds as potential permeability-increasing agents against B. cepacia.

Bactericidal efficacy of liposomal aminoglycosides against Burkholderia cenocepacia

“…2 Pulmonary colonization with B. cepacia in CF patients is associated with high morbidity and mortality, 3,4 as this complex is inherently resistant to several antimicrobial agents, including aminoglycosides. 5 Liposomes are spherical phospholipid bilayers that can be loaded with mediators such as vaccines and antibiotics for safe delivery to the action site. For instance, antifungal antibiotics are able to overcome fungus resistance when they are carried by liposomes.…”

Identification of Hopanoid Biosynthesis Genes Involved in Polymyxin Resistance in Burkholderia multivorans

“…Although cationic peptides and antibiotics appear to be unable to kill Bcc organisms, they may enhance the antimicrobial activity of other antibiotics (37,38), providing physicians with a broader spectrum of therapeutic options for Bcc infections.…”

Improved Electrotransformation and Decreased Antibiotic Resistance of the Cystic Fibrosis Pathogen Burkholderia cenocepacia Strain J2315

“…In particular, clinical isolates of P. aeruginosa and strains of E. coli, S. Typhimurium, and the Gram-positive Staphylococcus aureus are sensitized to some antibiotics by spermine (23). Enhancement of antimicrobial susceptibility by chemical cationic compounds was reported for strains of B. cepacia while spermidine and cadaverine had no effect (spermine was not tested) (36). We have tested the effects of spermine on the growth and antibiotic sensitivity of J2315.…”