Structure−Function Studies of Polymyxin B Nonapeptide:  Implications to Sensitization of Gram-Negative Bacteria

Tsubery, Haim; Ofek, Itzhak; Cohen, SB; Fridkin, Mati

doi:10.1021/jm0000057

Cited by 143 publications

(146 citation statements)

References 27 publications

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“…It has long been believed that polymyxins elicit their bactericidal effects by binding to and disrupting the action of LPS, the major antigen of the outer membrane of Gram-negative bacteria (42). LPS contains three major structural components: lipid A, a core oligosaccharide, and an outer polysaccharide composed of repeating hetero-oligosaccharide subunits.…”

Section: Discussionmentioning

confidence: 99%

Isolation, Structural Characterization, and Properties of Mattacin (Polymyxin M), a Cyclic Peptide Antibiotic Produced byPaenibacillus kobensis M

Martin

Moake

et al. 2003

Journal of Biological Chemistry

104

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Mattacin is a nonribosomally synthesized, decapeptide antibiotic produced by Paenibacillus kobensis M. The producing strain was isolated from a soil/manure sample and identified using 16 S rRNA sequence homology along with chemical and morphological characterization. An efficient production and isolation procedure was developed to afford pure mattacin. Structure elucidation using a combination of chemical degradation, multidimensional NMR studies (COSY, HMBC, HMQC, ROESY), and mass spectrometric (MALDI MS/MS) analyses showed that mattacin is identical to polymyxin M, an uncommon antibiotic reported previously in certain Bacillus species by Russian investigators. Mattacin (polymyxin M) is cyclic and possesses an amide linkage between the C-terminal threonine and the side chain amino group of the diaminobutyric acid residue at position 4. It contains an (S)-6-methyloctanoic acid moiety attached as an amide at the N-terminal amino group, one D-leucine, six L-␣,␥-diaminobutyric acid, and three L-threonine residues. Transfer NOE experiments on the conformational preferences of mattacin when bound to lipid A and microcalorimetry studies on binding to lipopolysaccharide showed that its behavior was very similar to that observed in previous studies of polymyxin B (a commercial antibiotic), suggesting an identical mechanism of action. It was capable of inhibiting the growth of a wide variety of Gram-positive and Gramnegative bacteria, including several human and plant pathogens with activity comparable with purified polymyxin B. The biosynthesis of mattacin was also examined briefly using transpositional mutagenesis by which 10 production mutants were obtained, revealing a set of genes involved in production.

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Section: Discussionmentioning

confidence: 99%

Isolation, Structural Characterization, and Properties of Mattacin (Polymyxin M), a Cyclic Peptide Antibiotic Produced byPaenibacillus kobensis M

Martin

Moake

et al. 2003

Journal of Biological Chemistry

104

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“…The only difference between PMB and PMBN is the absence of the 6-heptanoyl/octanoyl diaminobutyryl group at the amino terminus of the latter. This difference is responsible for the poor antiendotoxic activity of PMBN (58), despite apparent similarities in LPS binding ability (59). Therefore, we examined directly the antiendotoxic activity of histones H2A and H2B.…”

Section: Discussionmentioning

confidence: 99%

Endotoxin-Neutralizing Antimicrobial Proteins of the Human Placenta

Kim

Cho

Park

et al. 2002

The Journal of Immunology

119

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Microbial colonization and infection of placental tissues often lead to adverse pregnancy outcomes such as preterm birth, a leading cause of neonatal morbidity and mortality. The fetal membranes of the placenta, a physical and active barrier to microbial invasion, encapsulate the fetus and secure its intrauterine environment. To examine the innate defense system of the human placenta, antimicrobial peptides were isolated from the fetal membranes of human placenta and characterized biochemically. Two salt-resistant antimicrobial host proteins were purified to homogeneity using heparin-affinity and reversed-phase HPLC. Characterization of these proteins revealed that they are identical to histones H2A and H2B. Histones H2A and H2B showed dose-dependent inhibition of the endotoxin activity of LPS and inhibited this activity by binding to and therefore blocking both the core and lipid A moieties of LPS. Consistent with a role for histones in the establishment of placental innate defense, histones H2A and H2B were highly expressed in the cytoplasm of syncytiotrophoblasts and amnion cells, where the histone proteins were localized mainly to the epithelial surface. Furthermore, culturing of amnion-derived WISH cells led to the constitutive release of histone H2B, and histones H2A and H2B contribute to bactericidal activity of amniotic fluid. Our studies suggest that histones H2A and H2B may endow the epithelium of the placenta with an antimicrobial and endotoxin-neutralizing barrier against microorganisms that invade this immune-privileged site.

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“…However, this effect was inhibited by millimolar concentrations of MgCl 2 . PMBN also increased the susceptibility of Gram-negative microorganisms to hydrophobic antibiotics (248). To date, however, these compounds have not been successfully developed for the clinic; for example, PMBN failed due to toxicity.…”

Section: Outer Membrane Permeabilizersmentioning

confidence: 99%

Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance

2012

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SUMMARY The substantial use of antibiotics in the clinic, combined with a dearth of new antibiotic classes, has led to a gradual increase in the resistance of bacterial pathogens to these compounds. Among the various mechanisms by which bacteria endure the action of antibiotics, those affecting influx and efflux are of particular importance, as they limit the interaction of the drug with its intracellular targets and, consequently, its deleterious effects on the cell. This review evaluates the impact of porins and efflux pumps on two major types of resistance, namely, mutational and adaptive types of resistance, both of which are regarded as key phenomena in the global rise of antibiotic resistance among pathogenic microorganisms. In particular, we explain how adaptive and mutational events can dramatically influence the outcome of antibiotic therapy by altering the mechanisms of influx and efflux of antibiotics. The identification of porins and pumps as major resistance markers has opened new possibilities for the development of novel therapeutic strategies directed specifically against these mechanisms.

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Structure−Function Studies of Polymyxin B Nonapeptide: Implications to Sensitization of Gram-Negative Bacteria

Cited by 143 publications

References 27 publications

Isolation, Structural Characterization, and Properties of Mattacin (Polymyxin M), a Cyclic Peptide Antibiotic Produced byPaenibacillus kobensis M

Isolation, Structural Characterization, and Properties of Mattacin (Polymyxin M), a Cyclic Peptide Antibiotic Produced byPaenibacillus kobensis M

Endotoxin-Neutralizing Antimicrobial Proteins of the Human Placenta

Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance

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