Development of a CCL5-based lead compound for Staphylococcus aureus infection inhibition

Ministry of Education and Science - Grant Funding 2018-2020

Staphylococcus aureus is the cause of a large number of deadly infections worldwide and the emergence of antibiotic-resistant S. aureus strains represents a steadily increasing global threat. The bi-component pore-forming leukotoxin ED (LukED) is used by S. aureus to compromise the host immune system and cause deadly infectivity. LukE binds to human (and mouse) CCR5 on T cells, macrophages and dendritic cells; subsequently, a bi-component octamer formed by alternate LukE and LukD monomers assembles on the surface of target cells. The pores formed by LukED ultimately lead to cell death. CCR5 deficiency, and CCR5 antagonism (by maraviroc, MVC, a small chemical HIV-1 entry inhibitor), confer resistance to lethal S. aureus infection. CCL5, a natural ligand of CCR5 also has the ability to inhibit LukE and CCR5 interaction. CCL5 5p12 5m, a highly potent CCL5-based CCR5 antagonist (1000 fold more potent than MVC as HIV-1 inhibitor) developed by the PI, is likely to be a potent inhibitor of S. aureus LukED cytotoxic activity. We therefore plan to test CCL5 5p12 5m in cellular assays involving S. aureus (including antibiotic-resistant strain) and target macrophages, dendritic and T cells. We expect that CCL5 5p12 5m exerts a superior inhibitory activity as compared to MVC, setting the basis for the development of a novel lead compound in the fight to antibiotic resistance. Antibiotic-resistant S. aureus strains do not spare Kazakhstan, with numerous infections reported throughout the country, confirming the relevance of this project for global as well as national health.