Isopropoxy benzene guanidine kills Staphylococcus aureus without detectable resistance

AbstractAntibiotic resistance is a serious public health crisis. The challenge caused by Staphylococcus aureus infections clearly urges the development of novel antimicrobial therapy. Drug repurposing has emerged as an alternative approach to rapidly identify effective drugs against multidrug-resistant bacteria. Recently, substituted benzene guanidine compounds have been used as leading structures to discover new promising drugs in both synthetic and medicinal chemistry. We investigated the antimicrobial activity of an analog of substituted benzene guanidine compounds (isopropoxy benzene guanidine) and further explored its antibacterial mechanism against S. aureus. Isopropoxy benzene guanidine had a MIC of 0.125-4μg/ml against S. aureus and displayed potent activity against S. aureus by disrupting cell membrane. Unlike conventional antibiotics, repeated use of isopropoxy benzene guanidine had a low probability of resistance section. The most substantial isopropoxy benzene guanidine-induced changes occurred in transcript levels of membrane transport functions-regulated genes, and genes involved in purine- and pyrimidine-synthesis pathway and virulence factors. Furthermore, in vivo studies demonstrated that isopropoxy benzene guanidine is capable of treating invasive MRSA infections. These findings provided strong evidence that isopropoxy benzene guanidine represents a new chemical lead for novel antibacterial agent against multidrug-resistant S. aureus infections.