The efficacy of two polymyxin-like peptides, KFFKFFKFF and IKFLKFLKFL, alone and combined with levofloxacin, was investigated in a rat model of septic shock. Rats were given an ip injection of 2 x 10(10) cfu of Escherichia coli and randomized to receive ip isotonic sodium chloride solution, 7 mg/kg levofloxacin, 1 mg/kg polymyxin B and 1 mg/kg of each polymyxin-like peptides alone or combined with 7 mg/kg levofloxacin. Polymyxins achieved a significant reduction in plasma endotoxin and tumour necrosis factor alpha (TNF-alpha) concentration. Levofloxacin significantly reduced the bacterial growth and TNF-alpha concentration. The combinations of polymyxin-like peptides and levofloxacin demonstrated the highest efficacy.
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http://dx.doi.org/10.1093/jac/49.1.193 | DOI Listing |
Int J Mol Sci
May 2023
Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
Though the bulk of the COVID-19 pandemic is behind, the search for effective and safe anti-SARS-CoV-2 drugs continues to be relevant. A highly pursued approach for antiviral drug development involves targeting the viral spike (S) protein of SARS-CoV-2 to prevent its attachment to the cellular receptor ACE2. Here, we exploited the core structure of polymyxin B, a naturally occurring antibiotic, to design and synthesize unprecedented peptidomimetics (PMs), intended to target contemporarily two defined, non-overlapping regions of the S receptor-binding domain (RBD).
View Article and Find Full Text PDFPharmacol Rev
April 2021
Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Victoria, Australia (S.C.N., M.A.K.A., J.L.); Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia (T.V.); and Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana (Q.T.Z.)
Antibiotic resistance is a major global health challenge and, worryingly, several key Gram negative pathogens can become resistant to most currently available antibiotics. Polymyxins have been revived as a last-line therapeutic option for the treatment of infections caused by multidrug-resistant Gram negative bacteria, in particular , , and Enterobacterales. Polymyxins were first discovered in the late 1940s but were abandoned soon after their approval in the late 1950s as a result of toxicities (e.
View Article and Find Full Text PDFAdv Exp Med Biol
September 2019
Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, VIC, Australia.
The antimicrobial lipopeptides polymyxin B and colistin (polymyxin E) are used as a 'last-line' therapy for infections caused by multidrug-resistant (MDR) Gram-negative pathogens. However, their effective use as antibiotic drugs in the clinical setting is still plagued by significant toxicity issues, in particular their potential for nephrotoxicity. Furthermore, resistance to the polymyxins has begun to emerge in the clinic, which implies a total lack of antibiotics for the treatment of life-threatening infections caused by the Gram-negative 'superbugs'.
View Article and Find Full Text PDFAdv Exp Med Biol
September 2019
Biomedicine Discovery Institute, Infection & Immunity Program and Department of Microbiology, Monash University, Clayton Campus, Melbourne, VIC, Australia.
Polymyxin-induced nephrotoxicity is the major dose-limiting factor and can occur in up to 60% of patients after intravenous administration. This chapter reviews the latest literature on the mechanisms of polymyxin-induced nephrotoxicity and its amelioration. After filtration by glomeruli, polymyxins substantially accumulate in renal proximal tubules via receptor-mediated endocytosis mainly by megalin and PEPT2.
View Article and Find Full Text PDFNat Prod Rep
March 2017
Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, VIC, 3800, Australia.
Covering: 1975 up to the end of 2016The decline in the discovery and development of novel antibiotics has resulted in the emergence of bacteria that are resistant to almost all available antibiotics. Currently, polymyxin B and E (colistin) are being used as the last-line therapy against life-threatening infections, unfortunately resistance to polymyxins in both the community and hospital setting is becoming more common. Octapeptins are structurally related non-ribosomal lipopeptide antibiotics that do not exhibit cross-resistance with polymyxins and have a broader spectrum of activity that includes Gram-positive bacteria.
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