The research team led by Professor Yang Caiguang from the School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Studies, UCAS (hereinafter referred to as the HIAS School of Pharmaceutical Science and Technology) has made new progress in cooperation with the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences (CAS) in the anti-drug-resistant bacterial infection of Staphylococcus aureus ClpP activators. Their research findings were published online inNature Communications under the title "Anti-infective therapy using species-specific activatorsofStaphylococcus aureus ClpP" (IF = 17.694).
The discovery of antibiotics is generally recognized as one of the greatest achievements of the 20th century.It saves millions of lives every year and has extended the average life expectancy of human beings by 10 to 20 years. However, in recent decades, the R&D of antibiotics has entered a blank area of innovation, and the development of new mechanisms and new types of antibiotics has slowed down. In addition, antibiotics are abused by many people. All these factors have made antibiotic resistance against pathogenic bacteria one of the most serious global public health threats in the 21st century. The World Health Organization (WHO) has stressed that antibiotic resistance in clinical treatment could lead to 10 million deaths by 2050 if it continues to develop at the current rate. Therefore, it is urgent to find new targets and mechanisms different from the mode of action of conventional antibiotics, so as to promote the R&D of relevant antibacterial compounds.
Staphylococcus aureus (S. aureus) is one of the major bacteria that cause disease in humans.With the development of drug resistance, a variety of methicillin-resistantS. aureus (MRSA) has emerged, posing a significant threat to medical treatment and public health. Caseinolytic protease P (ClpP) is a highly conserved ATP-dependent serine hydrolase in prokaryotes and eukaryotes that regulates protein homeostasis. Studies have shown thatS. aureus ClpP (SaClpP) is a potential antibiotic target.Compared with conventional antibiotics that inhibit key proteins in bacteria, aberrant activation ofSaClpP will lead to excessive hydrolysis of key proteins inS. aureus and thus sterilization, which is a new strategy different from that of conventional antibiotics.However, sinceHomo sapiens ClpP (HsClpP) also exists in the mitochondria of the host, ideal antibiotic studies on targetingSaClpP must fully avoid interference withHsClpP in the host.However, no selectiveSaClpP activators have been reported yet.
In response to the above challenges, the research team of Yang Caiguang obtained two highly selective activators(R)- and(S)-ZG197 through high-throughput screening and structural optimization, combined with crystal analysis and sequence comparative analysis of the complexes of the two ClpP proteins, and by analyzing the structural differences of the amino acids of the two ClpP proteins.Biochemical experiments showed that it could selectively bind to and activateSaClpP but notHsClpP.The researchers further explained the mechanism of action of the two compounds to achieve selectivity through biophysical and biochemical methods and other means.At the bacterial level, small molecules have significant antibacterial activity against multiple strains of drug-resistant MRSA clinically isolated at home and abroad. Zebrafish and mice infection models were used as in vivo models at the animal level, and it was found that the compound could have a significant therapeutic effect on MRSA-infected zebrafish, and could significantly reduce theS. aureus load on the skin surface in the murine skin infection model. The therapeutic effect was comparable to that of vancomycin, an antibiotic used in the clinical treatment of drug-resistant bacterial infections.
Small molecule selectively activates the resistance ofSaClpP to drug-resistant bacterial infections
In this study, the researchers innovatively reported on the first case of selective SaClpP activators (R)- and(S)-ZG197, and revealed the mechanism by which small molecules achieve selectivity, conceptually validating the selective activation of ClpP proteins from two different species.The mechanism of action, targeting selectivity and anti-infective efficacy of antibiotics were comprehensively evaluated from molecular, cellular and animal levels.This work has the potential to provide promising strategies for the treatment of MRSA infections, providing a foundation and a new direction for clinical research on new types of antibiotics.
The first authors of this paper are Wei Bingyan, one of the first batch of doctoral candidates of theHIASSchool of Pharmaceutical Science and Technology, Dr. Zhang Tao, an associate research fellow of the Shanghai Institute of Materia Medica of the CAS, Dr. Wang Pengyu, a postdoctoral fellow of the HIAS School of Pharmaceutical Science and Technology. Yang Caiguang, Chief Professor of the HIAS School of Pharmaceutical Science and Technology, is the corresponding author. The research was supported by the Ji Quanjiang Research Group of ShanghaiTech University, Wu Wenjuan Research Group of Shanghai East Hospital, affiliated to Tongji University School of Medicine, Lan Lefu Research Group of Shanghai Institute of Materia Medica of the CAS, Gan Jianhua Research Group of Fudan University, Shanghai Synchrotron Radiation Facility, Shanghai Public Health Clinical Center, and the pilot project of compound resource bank of Shanghai Institute of Materia Medica of the CAS, and funded by the National Natural Science Foundation of China.
Source | School of Pharmaceutical Science and Technology
Editor | Xue Yawen
