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.

Department of Applied Chemistry University of Debrecen Debrecen 4032 Hungary

Department of Biotechnology Jožef Stefan Institute Jamova 39 1000 Ljubljana Slovenia

Department of Organic Chemistry University of Debrecen Debrecen 4032 Hungary

Department of Pharmaceutical Chemistry University of Debrecen Debrecen Egyetem tér 1 4032 Hungary

Doctoral School of Pharmaceutical Sciences University of Debrecen Debrecen Egyetem tér 1 4032 Hungary

Faculty of Pharmacy University of Ljubljana Aškerčeva cesta 7 1000 Ljubljana Slovenia

Faculty of Sciences Institute of Biology University of Pécs Pecs Ifjúság útja 6 7624 Hungary

Institute of Healthcare Industry University of Debrecen Debrecen Nagyerdei körút 98 4032 Hungary

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo nam 2 16000 Prague 6 Czech Republic

Laboratory for Biology of Secondary Metabolism Institute of Microbiology Academy of Sciences of the Czech Republic BIOCEV Průmyslová 595 252 50 Vestec Czech Republic

Medicinal Chemistry Research Group Research Centre for Natural Sciences Budapest Magyar tudósok krt 2 1117 Hungary

National Laboratory of Virology University of Pécs Pecs Ifjúság útja 20 7624 Hungary

Rega Institute for Medical Research KU Leuven 3000 Leuven Belgium

TargetEx Ltd Dunakeszi Madách Imre utca 31 2 2120 Hungary

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