Abstract
We report a series of synthetic cationic amphipathic barbiturates inspired by the pharmacophore model of small antimicrobial peptides (AMPs) and the marine antimicrobials eusynstyelamides. These N,N'-dialkylated-5,5-disubstituted barbiturates consist of an achiral barbiturate scaffold with two cationic groups and two lipophilic side chains. Minimum inhibitory concentrations of 2-8 μg/mL were achieved against 30 multi-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including isolates with extended spectrum β-lactamase-carbapenemase production. The guanidine barbiturate 7e (3,5-di-Br) demonstrated promising in vivo antibiotic efficacy in mice infected with clinical isolates of Escherichia coli and Klebsiella pneumoniae using a neutropenic peritonitis model. Mode of action studies showed a strong membrane disrupting effect and was supported by nuclear magnetic resonance and molecular dynamics simulations. The results express how the pharmacophore model of small AMPs and the structure of the marine eusynstyelamides can be used to design highly potent lead peptidomimetics against multi-resistant bacteria.
Highlights
There is a desperate need for developing new antimicrobial agents to meet the worldwide emergence and spread of resistant bacteria.[1]
In order to succeed transforming antimicrobial peptides (AMPs) with non-optimal pharmacokinetic properties into clinical useful antimicrobials, an innovative strategy is to develop synthetic mimics of AMPs (SMAMPs) with imperative functional side chains embodied on a peptidomimetic scaffold
We have in the present study developed a novel peptidomimetic scaffold that fulfills the pharmacophore model of small
Summary
There is a desperate need for developing new antimicrobial agents to meet the worldwide emergence and spread of resistant bacteria.[1] Resistant bacteria are currently causing deaths of 33,000 European patients annually, and the worst scenarios estimate 10 million deaths by 2050 per year if no measures are effectuated.[2,3] WHO announced in their Global action plan on antimicrobial resistance that access to and appropriate use of existing and new antimicrobial drugs are absolutely mandatory to maintain the ability to treat serious infections.[4] Increasing antimicrobial resistance has dramatic consequences for common medical interventions in cancer treatment, caesarean sections, and organ transplantations. Large pharmaceutical companies show little interest in antimicrobial drug development, mainly due to economic reasons. Academia and smaller research institutions are conceivably the most important contributors for discovery and synthesis of new lead compounds for antimicrobial drug development
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