Co-infection models of Staphylococcus aureus and respiratory viruses reveal synergistic interactions counteracted by a bithiazole derivative

Viral-bacterial co-infections represent a major contributor to global morbidity and mortality. In influenza virus infections, secondary bacterial pneumonia occurs in approximately 20–30% of cases and is associated with an increased risk of shock, mechanical ventilation, and even mortality. Bacterial superinfections are frequent causes of mortality in influenza severe infections and have been a major cause of morbidity and mortality also in COVID-19 patients. Staphylococcus aureus has been identified as one of the most prevalent bacterial pathogens among hospitalized and non-hospitalized patients who have tested positive for SARS-CoV-2 or influenza virus infections. Generally, antibiotic therapy is administered to at-risk patients to preclude bacterial over-infections by eliminating susceptible pathogens, increasing selective pressure favoring antibiotic-resistant bacteria. Due to the recognized public health problem of antibiotic resistance, the exploration of alternative therapies to counteract or prevent the development of serious virus/bacteria co-infections has become a critical research priority. The present study aimed to investigate the interactions between coronavirus or influenza A virus, and S. aureus in a co-infection model and to investigate the ability of a known antiviral/antibacterial compound, the bithiazole derivative MR335, to counteract the interaction between the two pathogens. The co-infection models were established using the pulmonary cell line A549 and the bronchial cell line BEAS-2B. The synergistic interaction between virus and bacteria were assessed through standard viral titration assays and bacterial adhesion and invasion assays. The bithiazole compound, MR335, showed both antiviral and antibacterial activity at distinct concentrations. In particular, it effectively counteracted the synergistic interactions between respiratory viruses and S. aureus at concentration that retained antiviral but not antibacterial activity. Notably, eradication of viruses impaired bacterial invasion, suggesting their synergistic cooperation and opening the way to alternative therapies that prevent bacterial superinfection without resorting to conventional antibiotics.