Semisynthetic teicoplanin derivatives with dual antimicrobial activity against SARS-CoV-2 and multiresistant bacteria.

Patients infected with SARS-CoV-2 risk co-infection with Gram-positive bacteria, which severely affects their prognosis. Antimicrobial drugs with dual antiviral and antibacterial activity would be very useful in this setting. Although glycopeptide antibiotics are well-known as strong antibacterial drugs, some of them are also active against RNA viruses like SARS-CoV-2. It has been shown that the antiviral and antibacterial efficacy can be enhanced by synthetic modifications. We here report the synthesis and biological evaluation of seven derivatives of teicoplanin bearing hydrophobic or superbasic side chain. All but one teicoplanin derivatives were effective in inhibiting SARS-CoV-2 replication in VeroE6 cells. One lipophilic and three perfluoroalkyl conjugates showed activity against SARS-CoV-2 in human Calu-3 cells and against HCoV-229E, an endemic human coronavirus, in HEL cells. Pseudovirus entry and enzyme inhibition assays established that the teicoplanin derivatives efficiently prevent the cathepsin-mediated endosomal entry of SARS-CoV-2, with some compounds inhibiting also the TMPRSS2-mediated surface entry route. The teicoplanin derivatives showed good to excellent activity against Gram-positive bacteria resistant to all approved glycopeptide antibiotics, due to their ability to dually bind to the bacterial membrane and cell-wall. To conclude, we identified three perfluoralkyl and one monoguanidine analog of teicoplanin as dual inhibitors of Gram-positive bacteria and SARS-CoV-2.

Teicoplanin-A New Use for an Old Drug in the COVID-19 Era?

Teicoplanin is an antibiotic that has been actively used in medical practice since 1986 to treat serious Gram-positive bacterial infections. Due to its efficiency and low cytotoxicity, teicoplanin has also been used for patients with complications, including pediatric and immunocompromised patients. Although teicoplanin is accepted as an antibacterial drug, its action against RNA viruses, including SARS-CoV2, has been proven in vitro. Here, we provide a thorough overview of teicoplanin usage in medicine, based on the current literature. We summarize infection sites treated with teicoplanin, concentrations of the antibiotic in different organs, and side effects. Finally, we summarize all available data about the antiviral activity of teicoplanin. We believe that, due to the extensive experience of teicoplanin usage in clinical settings to treat bacterial infections and its demonstrated activity against SARS-CoV2, teicoplanin could become a drug of choice in the treatment of COVID-19 patients. Teicoplanin stops the replication of the virus and at the same time avoids the development of Gram-positive bacterial co-infections.

Role of membrane proteins in bacterial resistance to antimicrobial peptides.

Several natural antimicrobial peptides (AMPs), including the novel semisynthetic lipoglycopeptide antibiotics telavancin, dalbavancin, and oritavancin, have been approved for clinical use to address the growing problem of multiple antibiotic-resistant Gram-positive bacterial infections. Nevertheless, the efficacy of these antibiotics has already been compromised. The SARS-CoV-2 pandemic led to the increased clinical use of all antibiotics, further promoting the development of bacterial resistance. Therefore, it is critical to gain a deeper understanding of the role of resistance mechanisms to minimize the consequential risks of long-term antibiotic use and misuse. Here, we summarize for the first time the current knowledge of resistance mechanisms that have been shown to cause resistance to clinically used AMPs, with particular focus on membrane proteins that have been reported to interfere with the activity of AMPs by affecting the binding of AMPs to bacteria.