Contribution of Each Amino Acid Residue in Polymyxin B3 to Antimicrobial and Lipopolysaccharide Binding Activity

Kanazawa, Kazushi; Sato, Yuki; Ohki, Kazuhiro; Okimura, Keiko; Uchida, Yoshiki; Shindo, Mitsuno; Sakura, Naoki

doi:10.1248/cpb.57.240

Cited by 61 publications

(91 citation statements)

References 21 publications

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“…The functional significance, in terms of antimicrobial and LPS neutralization activities of these Dab residues had been evaluated. 42,[73][74][75][76] Results obtained from this work can be correlated with the antimicrobial and anti-endotoxic activities of PMB. AMPs would interact with the LPS layer of the outer membrane causing disruption of the permeability barrier.…”

Section: Discussionmentioning

confidence: 68%

“…48 Replacements of D-Phe6 and Leu7 with other residues had caused significant loss of antimicrobial activities and LPS binding of PMB. 73,74,76 The N-terminus lipidic MO chain of PMB has been known for its involvement in disruption at the outer membrane and antimicrobial/antiendotoxic activities. 34 The CH 2 and CH 3 groups of MO appear to show different percentage of STD affects in LPS micelles, implying that the entire chain does not have similar proximity with LPS micelles (see Figure 10).…”

Section: Discussionmentioning

confidence: 99%

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Mapping residue-specific contacts of polymyxin B with lipopolysaccharide by saturation transfer difference NMR: Insights into outer-membrane disruption and endotoxin neutralization

Bhunia

Bhattacharjya

2011

Biopolymers

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High-resolution interactions studies of molecules with lipopolysaccharide (LPS) or endotoxin are important for health, diseases and environment. LPS is the major constituent of the outer layer of the outer membrane of the gram-negative bacteria. LPS provides an efficient barrier against permeation of variety of compounds including antibacterial agents and antimicrobial peptides. In the intensive care units, LPS is known for the fatal septic shock syndromes. Because of LPS toxicity, high affinity LPS sensors are sought-after for the assessment of the quality of water and pharmaceutical products. Therefore, elucidation of binding epitopes of LPS interacting molecules would be vital for the development of antimicrobial, antiendotoxic molecules. Polymyxin B (PMB), an antibacterial cyclic lipo-peptide, is well known for its LPS sequestering and neutralizing activities. Here, we have used saturation transfer difference (STD) NMR methods for characterizing interactions of PMB with LPS from E. coli 0111:B4 and P. aeruginosa. The dissociation constants of the LPS-PMB complexes were obtained from concentration dependent STD studies. Further a detailed epitope mapping of PMB has been carried out in E. coli 0111:B4 LPS micelles. Experiments including one-dimensional 1H STD, two-dimensional 1H-1H STD-TOCSY and naturalabundance 13C-1H STD-HSQC, are performed to determine the site(s) of interactions of PMB with endotoxin at atomic resolution. Our studies reveal that the hydrophobic sidechains of PMB including a part of the N-terminus lipidic tail demonstrate close contacts with LPS. In contrast, cyclic backbone structure of PMB has the lowest STD effects suggesting a rather loose association with endotoxin.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Mapping residue-specific contacts of polymyxin B with lipopolysaccharide by saturation transfer difference NMR: Insights into outer-membrane disruption and endotoxin neutralization

Bhunia

Bhattacharjya

2011

Biopolymers

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“…The bactericidal effect of polymyxin B is mediated through its positively charged DAB (␣,␥-diaminobutyric acid) residues interacting with lipopolysaccharide and destabilizing the outer membrane (7). Many antimicrobial peptides kill in a similar way: clustered cationic residues permeabilize the bacterial membrane to cause lysis and death (8).…”

mentioning

confidence: 99%

Novel Engineered Peptides of a Phage Lysin as Effective Antimicrobials against Multidrug-Resistant Acinetobacter baumannii

Thandar

Lood

Winer

et al. 2016

Antimicrob Agents Chemother

108

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Acinetobacter baumannii is a Gram-negative bacterial pathogen responsible for a range of nosocomial infections. The recent rise and spread of multidrug-resistant A. baumannii clones has fueled a search for alternative therapies, including bacteriophage endolysins with potent antibacterial activities. A common feature of these lysins is the presence of a highly positively charged C-terminal domain with a likely role in promoting outer membrane penetration. In the present study, we show that the C-terminal amino acids 108 to 138 of phage lysin PlyF307, named P307, alone were sufficient to kill A. baumannii (>3 logs). Furthermore, P307 could be engineered for improved activity, the most active derivative being P307 SQ-8C (>5-log kill). Both P307 and P307 SQ-8C showed high in vitro activity against A. baumannii in biofilms. Moreover, P307 SQ-8C exhibited MICs comparable to those of levofloxacin and ceftazidime and acted synergistically with polymyxin B. Although the peptides were shown to kill by disrupting the bacterial cytoplasmic membrane, they did not lyse human red blood cells or B cells; however, serum was found to be inhibitory to lytic activity. In a murine model of A. baumannii skin infection, P307 SQ-8C reduced the bacterial burden by ϳ2 logs in 2 h. This study demonstrates the prospect of using peptide derivatives from bacteriophage lysins to treat topical infections and remove biofilms caused by Gram-negative pathogens.

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“…Further the cyclic core alone (PMB 4-10; PMB heptapeptide 3d) retains substantial ability to permeabilise the outer membrane. 53 Kanazawa et al 46 further investigated the roles of the individual amino acids of Polymyxin by alanine scanning and confirmed the importance of the diaminobutyrate (Dab) residues in the cyclic core as would be expected from the model of Mares et al 33 These early findings have guided the design of next generation polymyxins.…”

Section: Development Of New Polymyxinsmentioning

confidence: 85%

Development of new polymyxin derivatives for multi-drug resistant Gram-negative infections

Brown¹,

Dawson²

2017

J Antibiot

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Over the last decade, there has been a resurgence of interest in polymyxins owing to the rapid rise in multi-drug resistant Gram-negative bacteria against which polymyxins offer a last-resort treatment. Although having excellent antibacterial activity, the clinical utility of polymyxins is limited by toxicity, especially renal toxicity. There is much interest therefore in developing polymyxin analogues with an improved therapeutic index. This review describes recent work aimed at improving the activity and/or reducing the toxicity of polymyxins. Consideration to providing activity against emerging strains with reduced susceptibility to polymyxins is also made.

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Contribution of Each Amino Acid Residue in Polymyxin B3 to Antimicrobial and Lipopolysaccharide Binding Activity

Cited by 61 publications

References 21 publications

Mapping residue-specific contacts of polymyxin B with lipopolysaccharide by saturation transfer difference NMR: Insights into outer-membrane disruption and endotoxin neutralization

Mapping residue-specific contacts of polymyxin B with lipopolysaccharide by saturation transfer difference NMR: Insights into outer-membrane disruption and endotoxin neutralization

Novel Engineered Peptides of a Phage Lysin as Effective Antimicrobials against Multidrug-Resistant Acinetobacter baumannii

Development of new polymyxin derivatives for multi-drug resistant Gram-negative infections

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