Semisynthetic Flavone-Derived Antimicrobials with Therapeutic Potential against Methicillin-Resistant Staphylococcus aureus (MRSA)

Abstract

A new series of semisynthetic flavone-based small molecules mimicking antimicrobial peptides has been designed from natural icaritin to combat drug-resistant Gram-positive bacterial infections. Compound 6 containing two arginine residues exhibited excellent antibacterial activity against Gram-positive bacteria, including MRSA, and very low toxicity to mammalian cells, resulting in a high selectivity of more than 511, comparable to that of several membrane-active antibiotics in clinical trials. Our data show for the first time that icaritin derivatives effectively kill bacteria. Meanwhile, this is the first study deploying a biomimicking strategy to design potent flavone-based membrane targeting antimicrobials. 6 showed rapid bactericidal activity by disrupting the bacterial membrane and can circumvent the development of bacterial resistance. Importantly, 6 was highly efficacious in a mouse model of corneal infection caused by MRSA and Staphylococcus aureus.

Study of Benzofuroquinolinium Derivatives as a New Class of Potent Antibacterial Agent and the Mode of Inhibition Targeting FtsZ

“…The drug resistance study of compound 1 – 5 was performed by following the protocol of previous study ( Lin et al, 2017 ). The initial MIC values of Compound 1–5 and methicillin against S. aureus ATCC 29213 were determined according to method described above.…”

Gentisaldehyde and Its Derivative 2,3-Dihydroxybenzaldehyde Show Antimicrobial Activities Against Bovine Mastitis Staphylococcus aureus

“…The increasing rate of bacteria resistant to antibiotics and antiseptics poses a major problem to human and veterinary health. Consequently, there is a desperate demand for novel antimicrobial agents active against resistant bacteria ( 8 , 12 , 29 ). In recognition of this requirement, this study investigated alternative antimicrobial compounds that might be suitable for the prevention of bovine mastitis.…”

“…The first choice antimicrobial agent for the treatment of S. aureus mastitis is penicillin G and in the case of beta-lactamase-producing and therefore penicillin-resistant strains, macrolides such as tylosin or isoxazolylpenicillins such as cloxacillin ( 5 , 6 ). The growing prevalence of antibiotic resistant bacteria leading to treatment failures is a major health problem ( 7 , 8 ). Therefore there is an increasing need for alternative methods such as hygiene optimization, the improvement of animal health using feed additives and the use of vaccines to manage infectious diseases in livestock ( 7 ).…”

“…Additionally, a high prevalence of genes responsible for benzalkonium chloride- and chlorhexidine-resistances has also been discovered in human S. aureus isolates ( 13 ). Thus, novel antimicrobial substances are urgently required ( 8 ). Historically natural sources such as soil microorganisms (bacteria, fungi) have been of special importance for the development of novel antimicrobials ( 14 – 17 ).…”

The Mycobacterial Membrane: A Novel Target Space for Anti-tubercular Drugs

“…Despite several appealing properties (rapid killing, low immunogenicity, uptake by macrophages, immunomodulatory properties) which render AMPs highly attractive as antimycobacterial candidates, their clinical advancement has been hampered by stability and pharmacokinetic issues arising from their peptidic character (Arranz-Trullén et al, 2017 ). Non-peptidic membrane targeting small molecules would arguably overcome these limitations and several such entities have been investigated against Gram-positive and Gram-negative bacteria with promising outcomes (Vooturi et al, 2009 , 2011 ; Eun et al, 2012 ; Zou et al, 2013 ; Hurley et al, 2015 ; Faulkner et al, 2016 ; Koh et al, 2016a ; Wang et al, 2016 ; Shuimu et al, 2017 ; Su et al, 2017 ). In comparison, the concept of damaging the structure of mycobacterial membrane bilayer as a therapeutic strategy has received less attention.…”