Phenylthiazole Antibacterial Agents Targeting Cell Wall Synthesis Exhibit Potent Activity in Vitro and in Vivo against Vancomycin-Resistant Enterococci

The
emergence of antibiotic-resistant bacterial species, such as
vancomycin-resistant enterococci (VRE), necessitates the development
of new antimicrobials. Here, we investigate the spectrum of antibacterial
activity of three phenylthiazole-substituted aminoguanidines. These
compounds possess potent activity against VRE, inhibiting growth of
clinical isolates at concentrations as low as 0.5 μg/mL. The
compounds exerted a rapid bactericidal effect, targeting cell wall
synthesis. Transposon mutagenesis suggested three possible targets:
YubA, YubB (undecaprenyl diphosphate phosphatase (UPPP)), and YubD.
Both UPPP as well as undecaprenyl diphosphate synthase were inhibited
by compound 1. YubA and YubD are annotated as transporters
and may also be targets because 1 collapsed the proton
motive force in membrane vesicles. Using Caenorhabditis
elegans, we demonstrate that two compounds (1, 3, at 20 μg/mL) retain potent activity
in vivo, significantly reducing the burden of VRE in infected worms.
Taken altogether, the results indicate that compounds 1 and 3 warrant further investigation as novel antibacterial
agents against drug-resistant enterococci.

耐万古霉素肠球菌（vancomycin-resistant enterococci, VRE）等耐药细菌菌株的出现，推动了新型抗菌药物的研发需求。本研究针对三种苯基噻唑取代氨基胍类化合物的抗菌活性谱展开探究。此类化合物对VRE展现出强效抗菌活性，仅需低至0.5 μg/mL的浓度即可抑制临床分离株的生长。该类化合物可快速发挥杀菌作用，靶点为细菌细胞壁合成通路。转座子诱变实验提示存在三个潜在作用靶点：YubA、YubB（十一异戊烯二磷酸磷酸酶（undecaprenyl diphosphate phosphatase, UPPP））以及YubD。化合物1可抑制UPPP与十一异戊烯二磷酸合酶的活性。YubA与YubD被注释为转运蛋白，同样可能为作用靶点，这是因为化合物1可破坏膜囊泡中的质子动力势。本研究利用秀丽隐杆线虫（Caenorhabditis elegans）模型证实，两种化合物（1、3，浓度为20 μg/mL）在体内仍保有强效抗菌活性，可显著降低感染线虫体内的VRE载量。综合来看，上述结果表明化合物1与3可作为抗耐药肠球菌的新型抗菌制剂，值得开展进一步研究。