Development of Des-Fatty Acyl-Polymyxin B Decapeptide Analogs with Pseudomonas aeruginosa-Specific Antimicrobial Activity

Katsuma, Naoko; Sato, Yuki; Ohki, Kazuhiro; Okimura, Keiko; Ohnishi, Kouhei; Sakura, Naoki

doi:10.1248/cpb.57.332

Cited by 22 publications

(26 citation statements)

References 17 publications

(31 reference statements)

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“…It is noteworthy that the potent activity against P.aeruginosa displayed by the compounds (59, 60) 95 is not consistent with the observed correlation between the length of the N α fatty acyl chain and antimicrobial activity reported elsewhere 96,97. This observation can be potentially construed in terms of the differences in the lipid A fatty acyl chain composition across these bacteria which in turn confers different OM properties 95,98…”

Section: Sar Of Polymyxinsmentioning

confidence: 80%

Structure−Activity Relationships of Polymyxin Antibiotics

Velkov

Thompson²,

Nation³

et al. 2009

J. Med. Chem.

642

776

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Section: Sar Of Polymyxinsmentioning

confidence: 80%

Structure−Activity Relationships of Polymyxin Antibiotics

Velkov

Thompson²,

Nation³

et al. 2009

J. Med. Chem.

642

776

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“…Interestingly, the Cubist Pharmaceuticals polymyxin clinical candidate CB-182,804 contained a shorter N-terminal 2-chlorophenyl carbamate group, yet had comparable in vitro and in vivo antibacterial activity with polymyxin B and colistin [62]. Furthermore, there has been a recent report describing des-fatty acyl polymyxin analogs that display selective antimicrobial activity against P. aeruginosa [64]. …”

Section: Polymyxins: Last-line Therapy Against Gram-negative ‘Superbugs’mentioning

confidence: 99%

Pharmacology of Polymyxins: New Insights into an ‘Old‘ Class of Antibiotics

Velkov¹,

Roberts

Nation³

et al. 2013

Future Microbiol.

388

384

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Increasing antibiotic resistance in Gram-negative bacteria, particularly in Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, presents a global medical challenge. No new antibiotics will be available for these ‘superbugs’ in the near future due to the dry antibiotic discovery pipeline. Colistin and polymyxin B are increasingly used as the last-line therapeutic options for treatment of infections caused by multidrug-resistant Gram-negative bacteria. This article surveys the significant progress over the last decade in understanding polymyxin chemistry, mechanisms of antibacterial activity and resistance, structure–activity relationships and pharmacokinetics/pharmacodynamics. In the ‘Bad Bugs, No Drugs’ era, we must pursue structure–activity relationship-based approaches to develop novel polymyxin-like lipopeptides targeting polymyxin-resistant Gram-negative ‘superbugs’. Before new antibiotics become available, we must optimize the clinical use of polymyxins through the application of pharmacokinetic/pharmacodynamic principles, thereby minimizing the development of resistance.

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“…1). 13,17) The product was extensively purified by HPLC and gel-filtration prior to examination of its biological activity. The purity of the synthetic peptides was Ͼ98%.…”

Section: Resultsmentioning

confidence: 99%

“…These results show that small hydrophilic amino acids (Dap, Ser) at the N-terminal are essential for antimicrobial specificity towards P. aeruginosa. 17) We consider that shortening a single methylene in the side chain of Dab and/or Thr allows for the efficient interaction of the linear portion in PMB analogs with the negatively charged phosphate group. The differences may be related to the distance between the phosphate group in LPS and the linear portion of the PMB analog.…”

Section: Resultsmentioning

confidence: 99%