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.

• MeSH
• Anti-Bacterial Agents chemistry   MeSH
• Antiviral Agents chemistry   MeSH
• COVID-19 * MeSH
• Fluorocarbons * pharmacology   MeSH
• Glycopeptides chemistry   MeSH
• Gram-Positive Bacteria MeSH
• Cathepsins pharmacology   MeSH
• Humans MeSH
• SARS-CoV-2 MeSH
• Teicoplanin pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Antiviral Agents MeSH
• Fluorocarbons * MeSH
• Glycopeptides MeSH
• Cathepsins MeSH
• Teicoplanin MeSH

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.

• Keywords
• COVID-19, SARS-CoV2, antibiotic, bacteria, co-infection, dalbavancin, lipoglycopeptide antibiotic, teicoplanin,
• Publication type
• Journal Article MeSH
• Review MeSH

The increase in antibiotic resistance among Gram-positive bacteria underscores the urgent need to develop new antibiotics. New antibiotics should target actively growing susceptible bacteria that are resistant to clinically accepted antibiotics including bacteria that are not growing or are protected in a biofilm environment. In this paper, we compare the in vitro activities of two new semisynthetic glycopeptide antibiotics, MA79 and ERJ390, with two clinically used glycopeptide antibiotics-vancomycin and teicoplanin. The new antibiotics effectively killed not only exponentially growing cells of Staphylococcus aureus, but also cells in the stationary growth phase and biofilm.

• Keywords
• Staphylococcus aureus, antibiotic resistance, glycopeptide antibiotics, teicoplanin pseudoaglycon,
• Publication type
• Journal Article MeSH

vanZ, a member of the VanA glycopeptide resistance gene cluster, confers resistance to lipoglycopeptide antibiotics independent of cell wall precursor modification by the vanHAX genes. Orthologs of vanZ are present in the genomes of many clinically relevant bacteria, including Enterococcus faecium and Streptococcus pneumoniae; however, vanZ genes are absent in Staphylococcus aureus. Here, we show that the expression of enterococcal vanZ paralogs in S. aureus increases the minimal inhibitory concentrations of lipoglycopeptide antibiotics teicoplanin, dalbavancin, oritavancin and new teicoplanin pseudoaglycone derivatives. The reduction in the binding of fluorescently labeled teicoplanin to the cells suggests the mechanism of VanZ-mediated resistance. In addition, using a genomic vanZ gene knockout mutant of S. pneumoniae, we have shown that the ability of VanZ proteins to compromise the activity of lipoglycopeptide antibiotics by reducing their binding is a more general feature of VanZ-superfamily proteins.

• Keywords
• Staphylococcus aureus, Streptococcus pneumoniae, VanZ, antibiotic resistance, lipoglycopeptide antibiotics,
• Publication type
• Journal Article MeSH