A new strategy for total solid-phase synthesis of polymyxins

Xu, Weiliang; Cui, A-Long; Hu, Xinxin; You, Xuefu; Li, Zhuorong; Zheng, Ji‐Min

doi:10.1016/j.tetlet.2015.06.056

Cited by 26 publications

(38 citation statements)

References 22 publications

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“…A 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl derivative (5 × ; Figure 6) was chosen for further study. 5 × had MIC 50 and MIC 90 values against susceptible strains of E. coli, K. pneumoniae, P. aeruginosa and A. baumannii that were similar or twofold better than PMB. In a mouse thigh efficacy model, however, a 2-3 × higher fAUC/MIC was required to achieve the same reduction in bacterial counts as PMB.…”

Section: Development Of New Polymyxin Derivatives P Brown and Mj Dawsonmentioning

confidence: 96%

“…In a subsequent study, Sato et al 66 described further des-fatty acyl nonapeptides and even octapeptides. [Ser 3 ]-PMB(3-10) (3 g) was highlighted with a minimum inhibitory concentration (MIC) against P. aeruginosa of 2 μg ml − 1 compared with 1 μg ml − 1 for PMB and an LD 50 of 450 μmol kg − 1 . These compounds are considered Pseudomonas-specific antibiotics.…”

Section: Des-fatty Acyl Polymyxin B Analoguesmentioning

confidence: 99%

“…56 A urea linked 2-chlorophenyl derivative, CB-182 804 ( Figure 5) was selected for further development. The activity of CB-182 804 was explored against a wide range of clinical isolates and this compound was shown to have MIC 50 and MIC 90 values approximately one dilution (2 × ) less potent than PMB. 67 Efficacy was determined in thigh and lung infection models and was generally similar to PMB and colistin.…”

Section: Cb-182 804mentioning

confidence: 99%

“…NAB739 had MIC 50 and MIC 90 values within 2-4 × that of PMB against enterobacteriaceae but activity was somewhat reduced against Acinetobacter spp. (4 × less potent than PMB) and especially P. aeruginosa (MIC 90 16 μg ml − 1 cf 2 μg ml − 1 for PMB).…”

Section: Direct Acting Derivatives With a Reduced Number Of Positive mentioning

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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Section: Development Of New Polymyxin Derivatives P Brown and Mj Dawsonmentioning

confidence: 96%

Section: Des-fatty Acyl Polymyxin B Analoguesmentioning

confidence: 99%

Section: Cb-182 804mentioning

confidence: 99%

Section: Direct Acting Derivatives With a Reduced Number Of Positive mentioning

confidence: 99%

See 2 more Smart Citations

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

Brown¹,

Dawson²

2017

J Antibiot

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show abstract

“…A powerful antibiotic that is representative of the head to side chain cycle topology is the polymyxin family. Polymyxin antibiotics are isolated from the Gram‐positive bacterium Paenibacillus polymyxa , also known as B. polymyxa , and comprise various analogues, such as polymyxin B (PMB) and polymyxin E2 (colistin B ( 4 ); Figure ) . Colistin is rich in the non‐proteinogenic amino acid Dab; thus conferring the molecule with additional stability against enzymatic degradation.…”

Section: Bacterial Antimicrobial Cyclopeptidesmentioning

confidence: 99%

Bacteria Hunt Bacteria through an Intriguing Cyclic Peptide

et al. 2018

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In the last few decades, peptides have been victorious over small molecules as therapeutics due to their broad range of applications, high biological activity, and high specificity. However, the main challenges to overcome if peptides are to become effective drugs is their low oral bioavailability and instability under physiological conditions. Cyclic peptides play a vital role in this context because they show higher stability under physiological conditions, higher membrane permeability, and greater oral bioavailability than that of their corresponding linear analogues. In this regard, cyclic antimicrobial peptides (AMPs) have gained considerable attention in the field of novel antibiotic development. Bacterial strains produce cyclic AMPs through two pathways: ribosomal and nonribosomal. This review provides an overview of the chemical classification of cyclic AMPs isolated from bacteria, and provides a description of their biological activity and mode of action.

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Polymyxins as Antibacterials and Antibiotic Potentiators

Dawson

Lister

2021

Burger's Medicinal Chemistry and Drug Discovery

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Antibiotic resistance in Gram‐negative pathogenic bacteria has reached alarming levels and these drug‐resistant bacteria pose an urgent global threat. All of the major classes of antibiotics with activity against Gram‐negative bacteria, including penicillins, cephalosporins, carbapenems, aminoglycosides, quinolones, and tetracyclines, have over time succumbed to widespread resistance. Fortunately, medicinal chemistry has been very successful at iteratively addressing the emergence of resistance (and other limitations) with second and third (or more) generation products. The polymyxin class has broad Gram‐negative antimicrobial activity, including against bacteria resistant to the antibiotic classes listed above. It is because of such activity that polymyxins have witnessed a resurgence in clinical use, but toxicity is concerning and commonly limits dosing. And, unlike other classes of antibiotics, the polymyxin class has been recalcitrant to clinically meaningful optimization and only the initially discovered, natural polymyxins are available for clinical use. This article explores recent developments in polymyxin‐based drug discovery and development and the extensive effort invested in trying to identify clinically viable second‐generation variants.

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A new strategy for total solid-phase synthesis of polymyxins

Cited by 26 publications

References 22 publications

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

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

Bacteria Hunt Bacteria through an Intriguing Cyclic Peptide

Polymyxins as Antibacterials and Antibiotic Potentiators

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