![]() 16,17 Based on these previous studies, we observed that the bifunctional cross linkage can modulate the antimicrobial activities of the synthetic multimers. 14,15 Additionally, multimerization of Chex1-Arg20 can further broaden its spectrum of activity as well as increase its antibacterial activity. 11–13 We previously applied several chemical modifications on the de novo designed PrAMP, Chex1-Arg20, with different terminal functional moieties to broaden its antibacterial spectrum. ![]() 10 Proline-rich AMPs (PrAMPs) are considered a promising class of candidates for rational design to target Gram-negative pathogens due to their low toxicity and multiple intracellular targets, such as DnaK and the bacterial ribosome. These have been comprehensively summarised in our recent review. 9 Since their discovery a century ago, various chemical modifications of AMPs have been applied to increase or enhance their potency against target microbes. 8ĭue to their multimodal action and broad potency antimicrobial peptides (AMPs), primarily host defense peptides, have demonstrated significant antibacterial activity against a range of multi-drug resistant (MDR) pathogens labelled as “superbugs”. 6 In 2018, the WHO identified a critical priority list calling for the development of new antibiotics against three Gram-negative bacteria, including Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae 7 Various strategies, including peptides, vaccines, probiotics, engineered bacteriophages and adjuvants, have been investigated to identify and develop novel antibacterial therapies. To date, the antibiotic market remains stocked with classical antibacterial drugs with slight chemical variations on existing antibiotic classes. ![]() 5 With limited revenues from antibiotic investment, many big pharmaceutical firms have redirected their antimicrobial research programs to more profitable fields such as anticancer drugs. 4 A recent economic model for evaluating the global cost of a newly developed active antibiotic with FDA approval was estimated at US$1.58 billion, excluding the marketing and surveillance after approval. 3 The ongoing COVID-19 pandemic is further constricting the pipeline of antimicrobials to handle bacterial infections and highlights the critical need for novel treatments by antibacterial agents. 1,2 The O'Neill report estimates deaths caused by AMR will exceed 10 million by 2050. Introduction Since the discovery of penicillin and subsequent antibiotics, the increasing global consumption of such wonder drugs has played a critical role in driving antimicrobial resistance (AMR) at an alarming rate in the last two decades as assessed by the World Health Organization (WHO). These findings highlight the advantages of use of such bifunctional tethers to produce first-in-class, potent PrAMP dimers against MDR/XDR bacterial infections. Molecular dynamics simulations of adsorption and permeation mechanisms of the PrAMP on a mixed lipid membrane bilayer showed that a rigid, planar tethered dimer orientation, together with the presence of fluorine atoms that provide increased bacterial membrane interaction, is critical for enhanced dimer activity. Additionally, 6 and 7 possess potent immunomodulatory activity and neutralise inflammation via nitric oxide production in macrophages. Mode of action studies indicated these lead PrAMPs can interact with both outer and inner bacterial membranes to affect the membrane potential and stress response. Greatest advantage was conferred using perfluoroaromatic linkers (tetrafluorobenzene and octofluorobiphenyl) with the resulting dimeric peptides 6 and 7 exhibiting potent action against Gram-negative bacteria, especially the World Health Organization's critical priority-listed multidrug-resistant (MDR)/extensively drug-resistant (XDR) Acinetobacter baumannii as well as preformed biofilms. Antibacterial assays confirmed that dimerization per se significantly enhances Chex1-Arg20 hydrazide action. Our current studies examined dimerization of the de novo designed proline-rich AMP (PrAMP), Chex1-Arg20 hydrazide, via C-terminal thiol addition to a series of bifunctional benzene or phenyl tethers to determine the effect of orientation of the peptides and linker length on antimicrobial activity. They are attractive lead molecules for rational development to improve their therapeutic index. Antimicrobial peptides (AMPs) are host defense peptides, and unlike conventional antibiotics, they possess potent broad spectrum activities and, induce little or no antimicrobial resistance.
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