The research team of the University of Hong Kong (HKU) has recently announced a breakthrough discovery using novel non-antibiotic drugs to treat Methicillin-resistant Staphylococcus aureus (MRSA) infections.

The indiscriminate use of antibiotics over the years has led to a rapid emergence of multidrug resistant (MDR) bacteria, with MRSA being one of them. MRSA renders commonly used antibiotics, including prophylactic antibiotics, ineffective. Scientists around the world have been in a desperate hunt for alternative strategies, as the growing threat of MRSA poses significant risk to orthopaedics and surgical procedures.

The revolutionary concept and discovery by the research team, hence, offers new hope in the battle against this deadly superbug, as well as other MDR bacteria. The groundbreaking concept to apply chemical genetics to tackle MRSA infection was claimed to be the world’s first. The study has snagged the 1st Prize accolade (Prix Hubert Tuor) of the Innovation Academy Award in the 4th International Conference on Prevention & Infection Control (ICPIC 2017) in Geneva, Switzerland. Findings of the study were recently published in mBio, the top international scientific journal in the field of Microbiology, in September 2017.

The significant health threat of MRSA in Hong Kong

According to the Department of Health (DH)’s statistics, the number of community-associated MRSA (CA-MRSA) cases has increased five-fold in the past nine years, with approximately 1,000 reports annually, in the recent three years.

Number of CA-MRSA cases recorded in Hong Kong. Source: Department of Health (2007 – 2016)
Number of CA-MRSA cases recorded in Hong Kong. Source: Department of Health (2007 – 2016)

Comparing to mainland China and overseas countries, S. aureus resistant to methicillin is at a high level in Hong Kong.

Percentage of resistant bacterial isolates in mainland China and overseas countries. Source: Hospital Authority Laboratory Data (2014) (Note: These data should be interpreted with caution due to variation in study methodology among different countries.)
Percentage of resistant bacterial isolates in mainland China and overseas countries. Source: Hospital Authority Laboratory Data (2014) (Note: These data should be interpreted with caution due to variation in study methodology among different countries.)

Apart from CA-MRSA, the Hong Kong Strategy and Action Plan on Antimicrobial Resistance (2017 – 2022) (Action Plan) has also highlighted high bed occupancy and limited space between beds might increase incidence of infection and the occurrence of outbreaks of MRSA in hospitals.

Breakthrough development of anti-virulence drugs against S. aureus

In order to look for new strategies to combat antimicrobial resistance, Prof Kwok-yung Yuen, top microbiologist at HKU, proposed and initiated an explorative research project in 2009. The project was then led by Dr Richard Kao Yi-tsun, Associate Professor of Department of Microbiology at the university.

Prof Yuen points out that the indiscriminately use of antibiotics has led to the rapid emergence of multidrug resistant bacteria including MRSA. Photo credit: Li Ka Shing Faculty of Medicine, University of Hong Kong
Prof Yuen points out that the indiscriminately use of antibiotics has led to the rapid emergence of multidrug resistant bacteria including MRSA. Photo credit: Li Ka Shing Faculty of Medicine, University of Hong Kong

To identify compounds which can reduce the virulence of MRSA, the research team screened more than 50,000 structurally diverse small molecule compounds. Eventually, a compound named NP16 by HKU was discovered to show strong inhibition on the production of staphyloxanthin, the golden-colored pigment in S. aureus, which has been known for its ability to promote bacterial invasion and contribute to the resistance to reactive oxygen species (ROS) and host neutrophil-based killing.

Using mutational studies and enzymatic assays coupled with Liquid chromatography–mass spectrometry (LC/MS), the research team was able to identify dehydrosqualene desaturase (CrtN) as the molecular target of NP16. The efficacy of NP16 in reducing MRSA virulence was further validated in in vitro cell-based tests and in in vivo animal studies.

ROS are employed by human phagocytic cells to eliminate bacteria and various invading pathogens. The staphyloxanthin expressed by S. aureus has a major protective function against these host defensive molecules. The research team has shown that the CrtN deletion mutant, which exhibited interrupted staphyloxanthin synthesis, was more sensitive to killing by purified human neutrophils and reduced virulence in mice MRSA infection models. This confirmed the importance of CrtN in in vivo survival of S. aureus.

Using increasing concentrations of NP16 can reduce the production of staphyloxanthin in methicillin resistant Staphylococcus aureus. Photo credit:  Li Ka Shing Faculty of Medicine, University of Hong Kong
Using increasing concentrations of NP16 can reduce the production of staphyloxanthin in methicillin resistant Staphylococcus aureus. Photo credit: Li Ka Shing Faculty of Medicine, University of Hong Kong

The research team discovered that the novel inhibitor NP16 of S. aureus pigment production has reduced the survival of S. aureus under oxidative stress conditions. S. aureus treated with NP16 has shown increased susceptibility to human neutrophil killing and to innate immune clearance in a mouse infection model. The study has also presented a potent and effective lead compound for the development of anti-virulence drugs against S. aureus, including the multidrug resistant MRSA.

“We believe that CrtN is a novel drug target for the virulence factor-based therapy against S. aureus. Compound NP16, as a potent CrtN inhibitor without direct bactericidal properties, renders the pathogen susceptible to normal host innate immune clearance on one hand, reduces the emergence of drug resistance on the other. Our approach of employing non-antibiotic drugs to treat MRSA infections by disarming the defensive shield of invading pathogens has offered new hope and new strategies for the treatment of bacterial infections related to multidrug resistant pathogens,” elaborated Kao.

Dr Kao says that the discovery of novel non-antibiotic drugs to treat MRSA infections by the HKU research team has offered new hope and new strategies for the treatment of bacterial infections related to multidrug resistant pathogens. Photo credit:  Li Ka Shing Faculty of Medicine, University of Hong Kong
Dr Kao says that the discovery of novel non-antibiotic drugs to treat MRSA infections by the HKU research team has offered new hope and new strategies for the treatment of bacterial infections related to multidrug resistant pathogens. Photo credit: Li Ka Shing Faculty of Medicine, University of Hong Kong

According to Kao, the research has been communicating with the government and a drug maker to explore potential possibilities to develop NP16 into a drug. Kao expected the pre-clinical research would take around three years – before they could test the drug on patients in clinical trials. MIMS

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