Discovery of Novel Polymyxin-Like Antibiotics

Velkov, Tony; Roberts, Kade D.

doi:10.1007/978-3-030-16373-0_20

Cited by 19 publications

(18 citation statements)

References 52 publications

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“…There are a number of major challenges in the discovery of novel polymyxins, including the complex PK/PD, lack of understanding on the mechanisms of toxicities (e.g., acute toxicity, nephrotoxicity, and hyperpigmentation), and narrow chemical space due to the closely related relationships between the structure, activity, PK, and toxicity. Nevertheless, significant progress has been made over the last decade in the discovery of novel, safer polymyxins with several groups working actively in the field ( Brown and Dawson, 2017 ; Vaara, 2019b ; Velkov and Roberts, 2019 ). One of the leading groups at Monash University is the first to employ structure-activity-PK-toxicity relationship based mechanistic models to design novel polymyxins that target polymyxin resistance in Gram negative bacteria with reduced nephrotoxicity in comparison with polymyxin B and colistin ( Velkov et al, 2014 , 2018b ; Velkov and Roberts, 2019 ).…”

Section: Current Landscape Of Polymyxin Drug Discoverymentioning

confidence: 99%

“…Nevertheless, significant progress has been made over the last decade in the discovery of novel, safer polymyxins with several groups working actively in the field ( Brown and Dawson, 2017 ; Vaara, 2019b ; Velkov and Roberts, 2019 ). One of the leading groups at Monash University is the first to employ structure-activity-PK-toxicity relationship based mechanistic models to design novel polymyxins that target polymyxin resistance in Gram negative bacteria with reduced nephrotoxicity in comparison with polymyxin B and colistin ( Velkov et al, 2014 , 2018b ; Velkov and Roberts, 2019 ). Their first-generation lipopeptide (FADDI-002) incorporated modifications of the core polymyxin scaffold ( Table 1 ) with l -octylglycine at position 7 to increase the hydrophobic interactions with lipid A, thereby circumventing polymyxin resistance as a result of the modifications of the lipid A phosphates.…”

Section: Current Landscape Of Polymyxin Drug Discoverymentioning

confidence: 99%

“…Pfizer (NY) also instigated a discovery program trying to alleviate polymyxin nephrotoxicity through modifications to the core and N -terminus of polymyxin B ( Velkov et al, 2016a ; Brown and Dawson, 2017 ; Velkov and Roberts, 2019 ). Through this work, it was demonstrated that lipopeptide 5a with the substitution of Dab3 with a diaminopropionic acid residue displayed a 2-fold improvement in MICs compared with polymyxin B against P .…”

Section: Current Landscape Of Polymyxin Drug Discoverymentioning

confidence: 99%

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Rescuing the Last-Line Polymyxins: Achievements and Challenges

et al. 2021

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Antibiotic resistance is a major global health challenge and, worryingly, several key Gram negative pathogens can become resistant to most currently available antibiotics. Polymyxins have been revived as a last-line therapeutic option for the treatment of infections caused by multidrug-resistant Gram negative bacteria, in particular Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacterales. Polymyxins were first discovered in the late 1940s but were abandoned soon after their approval in the late 1950s as a result of toxicities (e.g., nephrotoxicity) and the availability of “safer” antibiotics approved at that time. Therefore, knowledge on polymyxins had been scarce until recently, when enormous efforts have been made by several research teams around the world to elucidate the chemical, microbiological, pharmacokinetic/pharmacodynamic, and toxicological properties of polymyxins. One of the major achievements is the development of the first scientifically based dosage regimens for colistin that are crucial to ensure its safe and effective use in patients. Although the guideline has not been developed for polymyxin B, a large clinical trial is currently being conducted to optimize its clinical use. Importantly, several novel, safer polymyxin-like lipopeptides are developed to overcome the nephrotoxicity, poor efficacy against pulmonary infections, and narrow therapeutic windows of the currently used polymyxin B and colistin. This review discusses the latest achievements on polymyxins and highlights the major challenges ahead in optimizing their clinical use and discovering new-generation polymyxins. To save lives from the deadly infections caused by Gram negative “superbugs,” every effort must be made to improve the clinical utility of the last-line polymyxins. Significance Statement Antimicrobial resistance poses a significant threat to global health. The increasing prevalence of multidrug-resistant (MDR) bacterial infections has been highlighted by leading global health organizations and authorities. Polymyxins are a last-line defense against difficult-to-treat MDR Gram negative pathogens. Unfortunately, the pharmacological information on polymyxins was very limited until recently. This review provides a comprehensive overview on the major achievements and challenges in polymyxin pharmacology and clinical use and how the recent findings have been employed to improve clinical practice worldwide.

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Section: Current Landscape Of Polymyxin Drug Discoverymentioning

confidence: 99%

Section: Current Landscape Of Polymyxin Drug Discoverymentioning

confidence: 99%

Section: Current Landscape Of Polymyxin Drug Discoverymentioning

confidence: 99%

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Rescuing the Last-Line Polymyxins: Achievements and Challenges

et al. 2021

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“…Although the pursuit of the therapeutic application of many of these peptides had been abandoned over the last decade due to their inherent toxicity [53], we are now witnessing a revival of their use due to an increase in MDR infection occurrence. Today, some AMPs play an important role in the clinic, including colistin, which is considered the last resort against MDR pathogens [64]. In the following sub-sections, we briefly describe the main AMP classes from Table 1, and we refer the readers to existing recent reviews for further details.…”

Section: Antimicrobial Peptides (Amps) With D-amino Acidsmentioning

confidence: 99%

Polymer Conjugates of Antimicrobial Peptides (AMPs) with d-Amino Acids (d-aa): State of the Art and Future Opportunities

et al. 2022

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In recent years, antimicrobial peptides (AMPs) have enjoyed a renaissance, as the world is currently facing an emergency in terms of severe infections that evade antibiotics’ treatment. This is due to the increasing emergence and spread of resistance mechanisms. Covalent conjugation with polymers is an interesting strategy to modulate the pharmacokinetic profile of AMPs and enhance their biocompatibility profile. It can also be an effective approach to develop active coatings for medical implants and devices, and to avoid biofilm formation on their surface. In this concise review, we focus on the last 5 years’ progress in this area, pertaining in particular to AMPs that contain d-amino acids, as well as their role, and the advantages that may arise from their introduction into AMPs.

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“…Quite recently, international consensus derivatives that are more effective than the old ones and therefore could be used at lower, better tolerated doses. An excellent and comprehensive review on those attempts has recently been published [4].…”

Section: Introductionmentioning

confidence: 99%

Excretion of the Polymyxin Derivative NAB739 in Murine Urine

Vaara

Vaara²,

Kuka

et al. 2020

Antibiotics

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Extremely multiresistant strains of Enterobacteriaceae are emerging and spreading at a worrisome pace. Polymyxins are used as the last-resort therapy against such strains, in spite of their nephrotoxicity. We have previously shown that novel polymyxin derivatives NAB739 and NAB815 are less nephrotoxic in cynomolgus monkeys than polymyxin B and are therapeutic in murine Escherichia coli pyelonephritis at doses only one-tenth of that needed for polymyxin B. Here we evaluated whether the increased efficacy is due to increased excretion of NAB739 in urine. Mice were treated with NAB739 and polymyxin B four times subcutaneously at doses of 0.25, 0.5, 1, 2, and 4 mg/kg. In plasma, a clear dose–response relationship was observed. The linearity of Cmax with the dose was 0.9987 for NAB739 and 0.975 for polymyxin B. After administration of NAB739 at a dose of 0.25 mg/kg, its plasma concentrations at all tested time points were above 0.5 µg/mL while after administration at a dose of 0.5 mg/kg its plasma concentrations exceeded 1 µg/mL. The Cmax of NAB739 in plasma was up to 1.5-times higher after single (first) administration and up to two-times higher after the last administration when compared to polymyxin B. Polymyxin B was not detected in urine samples even when administered at 4 mg/kg. In contrast, the concentration of NAB739 in urine after single administration at a dose of 0.25 mg/kg was above 1 µg/mL and after administration of 0.5 mg/kg its average urine concentration exceeded 2 µg/mL. At the NAB739 dose of 4 mg/kg, the urinary concentrations were higher than 35 µg/mL. These differences explain our previous finding that NAB739 is much more efficacious than polymyxin B in the therapy of murine E. coli pyelonephritis.

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Discovery of Novel Polymyxin-Like Antibiotics

Cited by 19 publications

References 52 publications

Rescuing the Last-Line Polymyxins: Achievements and Challenges

Rescuing the Last-Line Polymyxins: Achievements and Challenges

Polymer Conjugates of Antimicrobial Peptides (AMPs) with d-Amino Acids (d-aa): State of the Art and Future Opportunities

Excretion of the Polymyxin Derivative NAB739 in Murine Urine

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