HKU investigators discover novel compound to treat methicillin-resistant Staphylococcus aureus infections
Scientists from the Department of Microbiology, The University of Hong Kong (HKU), recently discovered a compound called NP16, an inhibitor of dehydrosqualene desaturase, that is efficacious in treating Staphylococcus aureus infections.
Their recent study in mouse infection models demonstrated that when treated with the compound NP16, S. aureus showed increased susceptibility to killing by neutrophils and innate immune clearance. [mBio 2017, doi: https://doi.org/10.1128/mBio.01224-17]
In mice infected with S. aureus, treatment with NP16 resulted in significantly lower bacterial counts from harvested liver (p<0.05) and spleen (p<0.01) specimens vs treatment with vehicle control (phosphate buffered saline).
In vitro treatment of S. aureus with NP16 also resulted in reduction of the golden-coloured pigment produced by the microbe. Blocking the formation of this pigment significantly increased the susceptibility of the microbe to killing by exposure to 1.5 percent hydrogen peroxide.
NP16 was also shown to be non-toxic to various human cells, such as those coming from the lungs (A549 cell line), liver (Huh-7 cell line) and kidneys (293T and Vero cell lines).
“Compound NP16, a potent inhibitor of dehydrosqualene desaturase, disarms S. aureus, making the microbe susceptible to immune clearance and reducing drug resistance,” explained investigator Dr Richard Yi-Tsun Kao from the Department of Microbiology, HKU.
“Once synthesis of dehydrosqualene desaturase is inhibited, the microbe would not be capable of forming staphyloxanthin. Staphyloxanthin is a golden-coloured pigment contributing to the ability of S. aureus to resist killing by neutrophils and through the reactive oxygen species [ROS] pathway,” Kao added.
“Our platform enabled us to test the compound on human immune cells, ensuring its applicability in clinical practice in the future. Moreover, the compound specifically targets the enzyme of the microbe and would most probably not interfere with normal human metabolic processes,” commented Kao.
“We believe that it [dehydrosqualene desaturase] is a very important drug target to prevent resistance [to S. aureus], and we are hoping that this could be part of a drug development programme in Hong Kong or overseas in the near future,” he added.
Methicillin-resistant S. aureus (MRSA) infections in Hong Kong commonly occur in the hospital setting or in patients residing in long-term care facilities. Community-associated MRSA (CA-MRSA) infections have also been reported and can be transmitted through close contact or presence of skin lesions, such as cuts or abrasions. [http://www.chp.gov.hk/en/content/9/24/5392.html]
The study has been possible with the use of an automated high-throughput screening platform from the Chemical Genetics Unit of the Li Ka Shing Faculty of Medicine, HKU, which utilizes fully automated robotics technology optimized for cell-based screening assays.