Hasan Tükenmez, Taylor M. Nye, Pardeep Singh, Aaron Mychack, Mari Bonde, Suzanne Hickerson, Chloe L. P. Obernuefemann, Jerome S. Pinkner, 朱绍春, Souvik Sarkar, Jaideep B. Bharate, Ingeborg van der Lingen, Anh Quoc Ntuyenm, V. U. Bhaskara Rao, Anders E. G. Lindgren, Hanna Klein, Zongsen Zou, Karen Dodson, Suzanne Walker, André Mateus, Jörgen Johansson, Michael G. Caparon, Fredrik Almqvist, Scott J. Hultgren
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.