1. Synthesis of lipid A derivatives and their interactions with polymyxin B and polymyxin B nonapeptide
Ning Yin, Ryan L Marshall, Sannali Matheson, Paul B Savage J Am Chem Soc . 2003 Mar 5;125(9):2426-35. doi: 10.1021/ja0284456.
Lipid A is the causative agent of Gram-negative sepsis, a leading cause of mortality among hospitalized patients. Compounds that bind lipid A can limit its detrimental effects. Polymyxin B, a cationic peptide antibiotic, is one of the simplest molecules capable of selectively binding lipid A and may serve as a model for further development of lipid A binding agents. However, association of polymyxin B with lipid A is not fully understood, primarily due to the low solubility of lipid A in water and inhomogeneity of lipid A preparations. To better understand lipid A-polymyxin B interaction, pure lipid A derivatives were prepared with incrementally varied lipid chain lengths. These compounds proved to be more soluble in water than lipid A, with higher aggregation concentrations. Isothermal titration calorimetric studies of these lipid A derivatives with polymyxin B and polymyxin B nonapeptide indicate that binding stoichiometries (peptide to lipid A derivative) are less than 1 and that affinities of these binding partners correlate with the aggregation states of the lipid A derivatives. These studies also suggest that cooperative ionic interactions dominate association of polymyxin B and polymyxin B nonapeptide with lipid A.
2. Discerning the role of polymyxin B nonapeptide in restoring the antibacterial activity of azithromycin against antibiotic-resistant Escherichia coli
Saeed Tariq, Akela Ghazawi, Timothy Collyns, Farah Al-Marzooq, Lana Daoud Front Microbiol . 2022 Sep 21;13:998671. doi: 10.3389/fmicb.2022.998671.
Antimicrobial resistance is a global public health threat. Antibiotic development pipeline has few new drugs; therefore, using antibiotic adjuvants has been envisioned as a successful method to preserve existing medications to fight multidrug-resistant (MDR) pathogens. In this study, we investigated the synergistic effect of a polymyxin derivative known as polymyxin B nonapeptide (PMBN) with azithromycin (AZT). A total of 54Escherichia colistrains were first characterized for macrolide resistance genes, and susceptibility to different antibiotics, including AZT. A subset of 24 strains was then selected for synergy testing by the checkerboard assay. PMBN was able to re-sensitize the bacteria to AZT, even in strains with high minimum inhibitory concentrations (MIC: 32 to ≥128 μg/ml) for AZT, and in strains resistant to the last resort drugs such as colistin and meropenem. The fractional inhibitory concentration index was lower than 0.5, demonstrating that PMBN and AZT combinations had a synergistic effect. The combinations worked efficiently in strains carryingmphAgene encoding macrolide phosphotransferase which can cause macrolide inactivation. However, the combinations were inactive in strains having an additionalermBgene encoding macrolide methylase which causes ribosomal drug target alteration. Killing kinetics study showed a significant reduction of bacterial growth after 6 h of treatment with complete killing achieved after 24 h. Transmission electron microscopy showed morphological alterations in the bacteria treated with PMBN alone or in combination with AZT, with evidence of damage to the outer membrane. These results suggested that PMBN acted by increasing the permeability of bacterial outer membrane to AZT, which was also evident using a fluorometric assay. Using multiple antimicrobial agents could therefore be a promising strategy in the eradication of MDR bacteria. PMBN is a good candidate for use with other antibiotics to potentiate their activity, but further studies are requiredin vivo. This will significantly contribute to resolving antimicrobial resistance crisis.
3. Susceptibility of gram-negative bacteria to polymyxin B nonapeptide
P Viljanen, M Vaara Antimicrob Agents Chemother . 1984 Jun;25(6):701-5. doi: 10.1128/AAC.25.6.701.
Subinhibitory concentrations of polymyxin B nonapeptide sensitized all 21 polymyxin-susceptible gram-negative bacterial strains studied to hydrophobic antibiotics such as fusidic acid, novobiocin, and erythromycin. The susceptibility increases were usually 30- to 300-fold. The strains included representatives of Escherichia coli with different O- and K-antigens, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, Enterobacter agglomerans, Salmonella typhimurium, Acinetobacter calcoaceticus, Pseudomonas aeruginosa, and Pseudomonas maltophilia. In contrast, polymyxin-resistant strains (Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia stuartii, and Serratia marcescens) were resistant to the action of polymyxin B nonapeptide.
