Antibiotic resistance among pathogenic bacteria is an ever-increasing issue worldwide. Unfortunately, very little has been achieved in the pharmaceutical industry to combat this problem. This has led researchers and the medical field to revisit past drugs that were deemed too toxic for clinical use. In particular, the cyclic cationic peptides polymyxin B and colistin, which are specific for Gram-negative bacteria, have been used as "last resort" antimicrobials. Before the 1980s, these drugs were known for their renal and neural toxicities; however, new clinical practices and possibly improved manufacturing have made them safer to use. Previously suggested to primarily attack the membranes of Gram-negative bacteria and to not easily select for resistant mutants, recent research exploring resistance and mechanisms of action has provided new perspectives. This review focuses primarily on the proposed alternative mechanisms of action, known resistance mechanisms, and how these support the alternative mechanisms of action.

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Polymyxin: Alternative Mechanisms of Action and Resistance

Publisher Summary This chapter describes the isolation and assay procedures currently used in the study of the nine aminoglycoside-modifying enzymes. The enzymes—that modify the aminoglycoside or aminocyclitol antibiotics—have been detected in a wide variety of resistant bacteria. In many clinical isolates, they are known to be plasmid-coded. In certain strains, the enzymes appear to be located near the cell surface. The study of these enzymes is particularly valuable for two reasons. First, determination of the type and site of modification have allowed the design and synthesis of semisynthetic antibiotics not modified by the enzyme and therefore active against many resistant isolates. Second, the enzymes provide a very sensitive, rapid, and often specific assay for the aminoglycoside antibiotics. Enzyme activities are assayed by means of the phosphocellulose paper-binding assay, which measures transfer of radiolabel from a suitable cofactor to the antibiotic.

Aminoglycoside-modifying enzymes.

The mechanism of the antimicrobial action of oregano (Origanum compactum) and clove essential oils was studied simultaneously with two phenolic components, namely thymol and eugenol. Escherichia coli and Bacillus subtilis were used as Gram negative and Gram positive bacterial models, respectively. The oils as well as their major components were capable of inducing cell Iysis. Bacteria Iysis was shown by the release of substances absorbing at 260 nm. For E. coli, the results were similar to those obtained with polymyxin B. Scanning electronic microscope observations revealed that both cell wall and membrane of die treated bacteria were significantly damaged.

The Mechanism of Bactericidal Action of Oregano and Clove Essential Oils and of Their Phenolic Major Components on Escherichia coli and Bacillus subtilis

The outer membrane-disorganizing effect of a short (10-min) treatment with polycationic agents was studied with smooth Salmonella typhimurium used as a test organism. The polycationic agents were the protamine salmine, a lysine polymer with 20 lysine residues (lysine20), and the deacylated polymyxin B derivative polymyxin B nonapeptide. Two different types of outer membrane-disorganizing were found. Protamine and lysine20 released 20 to 30% of the lipopolysaccharide from the outer membrane and sensitized the bacteria to the anionic detergent sodium dodecyl sulfate but did not (under these conditions) make the bacteria permeable to the hydrophobic probes fusidic acid and actinomycin D. In contrast, polymyxin B nonapeptide did not release lipopolysaccharide or sensitize the bacteria to sodium dodecyl sulfate but made the outer membrane permeable to the hydrophobic probes. None of the agents was bactericidal under the conditions used or caused any leakage of periplasmic beta-lactamase. Polymyxin B was used as a reference and showed characteristic outer membrane-disorganizing action. In thin-section electron microscopy, polymyxin B nonapeptide caused the appearance of long, narrow, finger-like projections on the outer membrane. Protamine and lysine20 caused a distinctly wrinkled appearance of the outer membrane but no projections.

Polycations as outer membrane-disorganizing agents.

The effects of bacteria-nanoparticles interface on the antibacterial activity of green synthesized silver nanoparticles.

5 to 6% of the total cellular protein was released into the medium from Escherichia coli B which was harvested from a logarithmically growing culture in a glycerol-salts medium, suspended in 014 M NaCl, pH 73, at a tenfold cell density (about 15×1010/ml or 16 mg protein/ml) and treated for 1 min at 37° C with 200 μg polymyxin B/ml The protein patterns of this material obtained by polyacrylamide gel electrophoresis were identical with those derived from an osmotic shock supernatant according to Neu and Heppel (1965) Periplasmic enzyme activities found in the polymyxin-supernatant included 5′-nucleotidase, 3′-nucleotidase, ribonuclease I, acid phosphatase and alkaline phosphatase Upon further incubation with polymyxin B (up to 60 min), cell autolysis occurred with a concomitant release of 68% of total protein and up to 100% of cytoplasmic enzyme activities like β-galactosidase, inorganic pyrophosphatase and aldolase This autolysis was not observed with stationary phase cells or with cells grown in a complex yeast extract-glucose broth The mechanism of action of polymyxin B leading to the specific release of periplasmic proteins in discussed

Differential release of periplasmic versus cytoplasmic enzymes from Escherichia coli B by polymyxin B

Several cell-wall and membrane affecting agents were tested for causing release of periplasmic proteins of E coli B as compared by gel electrophoresis Osmotic shock and polymyxin-treatment yielded the best differentiated protein patterns The periplasmic proteins derived from different E coli strains and other gram-negative bacteria by polymyxin-treatment were compared Whereas related strains showed similarities in the protein positions, unrelated gram-negative bacteria showed great differences of the protein bands The polymyxin-induced liberation of periplasmic proteins was dependent upon the growth phase and growth media of the bacteria and was severely inhibited by 10-2 M magnesium chloride

Comparative polyacrylamide electrophoresis of periplasmic proteins released from gram-negative bacteria by polymyxin B.

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Differential release of periplasmic versus cytoplasmic enzymes from Escherichia coli B by polymyxin B

Comparative polyacrylamide electrophoresis of periplasmic proteins released from gram-negative bacteria by polymyxin B.