Synergistic Effect between Colistin and Bacteriocins in Controlling Gram-Negative Pathogens and Their Potential To Reduce Antibiotic Toxicity in Mammalian Epithelial Cells

Abstract

e Pathogens resistant to most conventional antibiotics are a harbinger of the need to discover novel antimicrobials and anti-infective agents and develop innovative strategies to combat them. The aim of this study was to assess the in vitro activity of colistin alone or in combination with two bacteriocins, nisin A and pediocin PA-1/AcH, against Salmonella choleraesuis ATCC 14028, Pseudomonas aeruginosa ATCC 27853, Yersinia enterocolitica ATCC 9610, and Escherichia coli ATCC 35150 (O157:H7). The strain most sensitive to colistin was enterohemorrhagic E. coli O157:H7, which was inhibited at a concentration of about 0.12 g/ml. When nisin A (1.70 g/ml) or pediocin PA-1/AcH (1.56 g/ml) was combined with colistin, the concentrations required to inhibit E. coli O157:H7 were 0.01 and 0.03 g/ml, respectively. The in vitro antigenotoxic effect of colistin was determined by using the comet assay method to measure the level of DNA damage in freshly isolated human peripheral blood leukocytes (PBLs) incubated with colistin for 1 h at 37°C. Changes in the tail extents of PBLs of about 69.29 ؎ 0.08 m were observed at a final colistin concentration of about 550 ng/ml. Besides the synergistic effect, the combination of colistin (1 mg/ml) and nisin (2 mg/ ml) permitted us to re-evaluate the toxic effect of colistin on Vero (monkey kidney epithelial) cells.T he emergence of multidrug-resistant pathogenic bacteria highlights a matching need for new therapeutic options. Better management and reasonable use of antibiotics are imperatively required in order to reduce the rate of emergence of antibioticresistant strains. Currently, clinicians and microbiologists are being forced to re-evaluate the clinical use of colistin, a relatively old polypeptide antibiotic, because there appear to be no promising therapeutic agents in the drug development pipeline (1). Colistin became available for clinical use in the 1960s but was replaced in the 1970s with antibiotics considered less toxic. Nephrotoxicity and neurotoxicity were the major side effects that led to the discontinuation of the routine use of colistin (1, 2). Two forms of colistin are commercially available, colistin sulfate, which is for oral and topical use, and colistimethate sodium (sodium colistin methanesulfonate, colistin sulfomethate sodium), which is for parenteral use or inhalation. The structure of polymyxins consists of a cyclic decapeptide bound to a fatty acid (3). Colistin binds to the anionic part of the lipopolysaccharide (LPS), leading to deep disruption in the bacterial membrane, enhancing its permeability and causing cell lysis (4). A role for LPS as a major receptor of colistin was proposed (5), and the mode of action involved a hydrophobic interaction between the nine-carbon fatty acid side chain of colistin and the fatty acid portion of lipid A (6). Strains of Escherichia coli and Klebsiella pneumoniae have become increasingly resistant to expanded-spectrum cephalosporins (7) but remain globally sensitive to tigecycline and colistin (8). The use of polymyxins t...

Evaluation of antibiotic releasing porous polymethylmethacrylate space maintainers in an infected composite tissue defect model

“…[23,24] Previous studies have shown that antibiotics, while intended to target bacteria, can have detrimental effects on viability and function of host cells in vitro. [25,26] This toxic effect seen in vitro could lead to breakdown of the soft tissue, fenestration, and dehiscence in vivo. It is also possible that the combination of gelatin and colistin may lead to increased local toxicity if the gelatin causes increased tissue exposure to colistin by retaining released colistin in the area.…”

Potential of Novel Antimicrobial Peptide P3 from Bovine Erythrocytes and Its Analogs To Disrupt Bacterial Membranes In Vitro and Display Activity against Drug-Resistant Bacteria in a Mouse Model

“…It is known that AMPs, including SMAP29 and LL-37, can permeabilize the bacterial cytoplasmic membrane (26,27), as did P3, which created many membrane pores in the E. coli membrane, in line with the barrel stave model (28). It is generally considered that AMPs exhibiting potent antimicrobial activities also have strong hemolytic and cytotoxic activities (29). However, hemolysis did not exceed 20% after treatment of red blood cells with P3 or its analogs at 400 g/ml, a concentration approximately 60-fold higher than the MIC.…”

Improved Antimicrobial Activities of Synthetic-Hybrid Bacteriocins Designed from Enterocin E50-52 and Pediocin PA-1

“…The potential of LAB bacteriocins in medical applications is exemplified by previously reported results which indicated that the oral intake of bacteriocin-producing LAB protects mice from lethal doses of Listeria monocytogenes (7). Therefore, LAB bacteriocins are the logical alternative to clinical antibiotics (8) and/or may help to enhance the efficacy of current antibiotics (9,10).…”