Science advances · 2026
Tunable TriPcides suppress virulence factor secretion during Staphylococcus aureus infection and kill dormant cells.
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Tükenmez Hasan, Nye Taylor M, Singh Pardeep, Mychack Aaron, Bonde Mari, Hickerson Suzanne, Obernuefemann Chloe L P, Pinkner Jerome S, Zhu Shaochun, Sarkar Souvik, Bharate Jaideep B, van der Lingen Ingeborg, Ntuyenm Anh Quoc, Rao V U Bhaskara, Lindgren Anders E G, Klein Hanna, Zou Zongsen, Dodson Karen W, Walker Suzanne, Mateus Andre, Johansson Jörgen, Caparon Michael G, Almqvist Fredrik, Hultgren Scott J
Аннотация
Antimicrobial resistance (AMR) in common bacterial pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), is an increasingly dire public health threat, with MRSA accounting for up to 90% of S. aureus infections. To expand the treatment arsenal against MRSA infections, we developed a class of tunable three-dimensional tricyclic 2-pyridones, termed TriPcides, that can kill MRSA resistant to last-resort antibiotics and eliminate MRSA persister cells. No preexisting resistance was detected across hundreds of clinical isolates, and continuous exposure of MRSA to TriPcides did not elicit detectable resistance. Treatment with TriPcides causes a rapid decrease in membrane integrity and increased levels of reactive oxygen species. Last, TriPcides effectively reduce secretion of important virulence factors and result in reduced ulcer size and healing time in S. aureus murine skin and soft tissue infections but do not reduce bacterial burden.