Design, Synthesis And Bioactivity Evaluation Of Less-Toxic And Highly Selective Antimicrobial Compounds

With the use and abuse of the broad-spectrum antibiotics,many multi-resistant bacteria have emerged.The severe antibiotic resistance has led to high motality and heathcare costs.Unfortunately,the research speed of antibacterial drugs is slower than that of drug-resistant bacteria.Therefore,the development of high-efficiency,low-toxic,non-resistant antibacterial compounds has become the main content of current antibacterial research.Research showed that Antimicrobial Peptides(AMPs)have good antibacterial activity,especially for multi-drug resistant bacteria,with no antibiotic resistance.Despite the many advantages,AMPs still have some disadvantages,including easy degradation,toxicity and a high cost of manufacture,which impedes the use of AMPs as clinical antibacterial agents.Antimicrobial peptide mimetics have been the focus of research in recent years.The problem needed to be solved is to use amphipathic models of AMPs to mimic the action of AMPs and thus produce membrane-targeting antimicrobial agents with high activity,low toxicity and no drug resistance.First,small molecular peptidomimetics were developed by taking advantage of the hydrophobic scaffold of chalcone.These molecules contained aromatic ring with different substituent group,and alkane chain with different length.Some compounds of this series exhibited potent antimicrobial properties against sensitive bacteria and drug-resistant bacteria.The MIC of compounds 2-5a and 2-5g were 1 and 0.5 ?g/mL against S.aureus,respectively.Compounds 2-5a and 2-5g also show low hemolytic toxicity and high selectivity.The structure-activity relationship indicates that the length of side chain and the position and number of fluorine atoms on the benzene can affect the antibacterial activity and hemolytic toxicity.Further biological experiment showed that leading compounds 2-5a and 2-5g possesses optimal attributes,such as stability in plasma;the ability to disintegrate established biofilms;little induction of drug resistance in treated bacteria;and no obvious toxicity.Mechanistic studies suggest that the antibacterial mechanism of action of these compounds involves depolarization of the cytoplasmic membrane and permeabilization of the inner/outer membrane,and then leading to bacterial death.Secondly,symmetrical compounds linked by an aromatic nucleus were synthesized.To study the effect of amide bond on activity,two small series were synthesized: amide compounds 3-4a~3-4w and non-amide compounds 3-5a~3-5p.To study the effects of symmetry and rigid structure on activity,compounds 3-6a~3-6h and 3-6i~3-6s were designed.Most compounds show better antibacterial activity,low hemolytic toxicity and high selectivity(selectivity of compounds 3-4g,3-5b,3-5n,3-6i,3-6n were 2438,> 2560,4844,> 2560,2036,respectively).Compounds 3-4a,3-4b,3-4g,3-4m,3-4r,3-4s,3-5b,3-5f,3-5j,3-5n,3-6i,3-6j,3-6n and 3-6r showed best antibacterial activity against clinical MRSA(MIC in the range of 0.25-4 ug/mL),KPC and NDM bacteria.The structure-activity relationship showed that the length of alkane chain,symmetry and rigid structure could affect the antibacterial activity and hemolytic toxicity.Further biological characterization of selected compounds 3-4g and 3-5n showed their stability in mammalian fluids;rapid bactericidal ability;no obvious drug-resistance was induced,and they can eradicate bacterial biofilms.Compound 3-5n have the best antibacterial activity,showed an equal effect to that of vancomycin in a mouse model of MRSA skin infection.In conclusion,87 small antimicrobial peptides mimics were designed and synthesized.Compounds 2-5a,2-5g,3-4g,and 3-5n showed best antibacterial activity,low toxicity and high selectivity.Further biological characterization has shown that antibacterial compounds not only hava the advantages of high antibacterial activity and non-drug resistance of AMPs,but also have the advantages of low toxicity,stability in mammalian fluids,convenient synthesis and low cost.