Structure−Activity Relationships of Polymyxin Antibiotics

Velkov, Tony; Thompson, Phillip E.; Nation, Roger L.; Li, Jian

doi:10.1021/jm900999h

Cited by 625 publications

(827 citation statements)

References 133 publications

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“…Colistin differs from polymyxin B by only one amino acid at position 6 in the peptide ring: a leucine in colistin and a phenylalanine in polymyxin B [22].…”

Section: Colistinmentioning

confidence: 99%

Old drug, new findings: colistin resistance and dependence of Acinetobacter baumannii

Choi

Lee

2017

Precis Future Med

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Colistin is an old drug, and its use has recently resurged because of increasing antibiotic resistance in gram-negative bacteria such as Acinetobacter baumannii. Although the colistin resistance rates in gram-negative bacteria are currently not high, many colistin-resistant isolates are being identified and the possibility of horizontal transmission of colistin resistance has increased because of the plasmid-borne colistin resistance gene mcr-1 (mobilized colistin resistance). In this review, we have discussed colistin resistance in A. baumannii. In addition, we have reviewed an abnormal phenomenon called colistin dependence in A. baumannii.

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“…Colistin differs from polymyxin B by only one amino acid at position 6 in the peptide ring: a leucine in colistin and a phenylalanine in polymyxin B [22].…”

Section: Colistinmentioning

confidence: 99%

Old drug, new findings: colistin resistance and dependence of Acinetobacter baumannii

Choi

Lee

2017

Precis Future Med

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“…The most frequent products are lipopeptides [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16], peptide/polyketide hybrids [17,18], as well as lantibiotics [19,20]. Such products qualify Paenibacillus strains for applications in agriculture, medicine, and biotechnology.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Novel Fusaricidins Produced by Paenibacillus polymyxa-M1 Using MALDI-TOF Mass Spectrometry

Vater

Niu

Dietel³

et al. 2015

J. Am. Soc. Mass Spectrom.

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Abstract. Paenibacillus polymyxa-M1 is a potent producer of bioactive compounds, such as lipopeptides, polyketides, and lantibiotics of biotechnological and medical interest. Genome sequencing revealed nine gene clusters for nonribosomal biosynthesis of such agents. Here we report on the investigation of the fusaricidins, a complex of cyclic lipopeptides containing 15-guanidino-3-hydroxypentadecanoic acid (GHPD) as fatty acid component by matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). More than 20 variants of these compounds were detected and characterized in detail. Mass spectrometric sequence analysis was performed by MALDI-LIFT-TOF/TOF fragment analysis. The obtained product ion spectra show a specific processing in the fatty acid part. GHPD is cleaved between the α-and ß-position yielding two fragments a and b, one bearing the end-standing guanidine group and another one comprising the residual two C-atoms of GHPD with the attached peptide moiety. The complete sequence of all fusaricidins was derived from sets of b n -and y n -ions. The fusaricidin complex can be divided into four lipopeptide families, three of them showing variations of the amino acid in position 3, Val or Ile for the first and Tyr or Phe for families 2 and 3, respectively. A collection of novel fusaricidins was detected differing from those of families 1-3 by an additional residue of 71 Da (family 4). LIFT-TOF/TOF fragment spectra of these species imply that in their peptide moiety, an Ala-residue is attached by an ester bond to the free hydroxyl group of Thr 4 . More than 10 novel fusaricidins were characterized mass spectrometrically.

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“…The early development of the structure-activity relationship (SAR) of polymyxins has been well described by Velkov et al 16 A key early finding of Vaara 34,60 was that PMB (2-10) (PMB nonapeptide 'PMBN'; 3b) retained the ability to permeabilise the outer membrane to ingress of dyes or hydrophobic antibiotics whilst having much reduced antibacterial activity. Further, this molecule had much reduced toxicity leading to a crude model that amino acids 2-10 are involved in LPS binding and permeabilisation whereas the N-terminal fatty-acyl moiety is crucial for bacterial killing, but also contributes significantly to the toxicity of the molecule against mammalian systems.…”

Section: Development Of New Polymyxinsmentioning

confidence: 99%

“…Earlier work in this area is reviewed by Velkov et al 16 As well as exploring acyl chain length, a wide range of aryl or cycloalkyl derivatives has been investigated and many derivatives retained good potency. There has, however, been no systematic evaluation of the effect on toxicity, particularly renal toxicity.…”

Section: Decapeptide Derivatives With An Altered N-terminal Acyl Chainmentioning

confidence: 99%

“…[11][12][13] Although we will briefly mention some recent advances with the currently available polymyxins, the focus of this review is on the development of next generation polymyxins designed to improve therapeutic index and to provide activity against strains with reduced susceptibility to current polymyxins. The reader's attention is drawn to two previous reviews by Professor Vaara as well as a thorough compilation of earlier work by Velkov et al [14][15][16] We will aim to update these reviews with more recent studies.…”

Section: Introductionmentioning

confidence: 99%

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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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Structure−Activity Relationships of Polymyxin Antibiotics

Cited by 625 publications

References 133 publications

Old drug, new findings: colistin resistance and dependence of Acinetobacter baumannii

Old drug, new findings: colistin resistance and dependence of Acinetobacter baumannii

Characterization of Novel Fusaricidins Produced by Paenibacillus polymyxa-M1 Using MALDI-TOF Mass Spectrometry

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

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