Tague Andrew J, Putsathit Papanin, Riley Thomas V, Keller Paul A, Pyne Stephen G
School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, New South Wales 2522, Australia.
School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia 6027, Australia.
ACS Med Chem Lett. 2021 Feb 3;12(3):413-419. doi: 10.1021/acsmedchemlett.0c00611. eCollection 2021 Mar 11.
Small-molecule antimicrobial peptidomimetic amphiphiles represent a promising class of novel antimicrobials with the potential for widespread therapeutic application. To investigate the role of spatial positioning for key hydrophobic and hydrophilic groups on the antimicrobial efficacy and selectivity, positional isomers of the lead biphenyl antimicrobial peptidomimetic compound were synthesized and subjected to microbial growth inhibition and mammalian toxicity assays. Positional isomer exhibited 4-8× increased efficacy against the pathogenic Gram-negative bacteria and (MIC = 2 μg/mL), while isomers , , and exhibited a 4× increase in activity against (MIC = 4 μg/mL). Changes in molecular shape had a significant impact on Gram-negative antibacterial efficacy and the resultant spectrum of activity, whereas all structural isomers exhibited significant efficacy (MIC = 0.25-8 μg/mL) against Gram-positive bacterial pathogens (e.g., methicillin-resistant , , and ).
小分子抗菌肽模拟两亲物是一类很有前景的新型抗菌剂，具有广泛治疗应用的潜力。为了研究关键疏水和亲水基团的空间定位对抗菌效力和选择性的作用，合成了先导联苯抗菌肽模拟化合物的位置异构体，并进行了微生物生长抑制和哺乳动物毒性试验。位置异构体对致病性革兰氏阴性菌和（最小抑菌浓度=2μg/mL）的效力提高了4-8倍，而异构体、和对（最小抑菌浓度=4μg/mL）的活性提高了4倍。分子形状的变化对革兰氏阴性菌抗菌效力和所得活性谱有显著影响，而所有结构异构体对革兰氏阳性菌病原体（如耐甲氧西林的、和）均表现出显著效力（最小抑菌浓度=0.25-8μg/mL）。
