Bacterial antimicrobial resistance (AMR) has emerged as one of the leading public health threats of the 21st century. In 2019, there were approximately 5 million deaths worldwide associated with bacterial AMR. According to the Review on Antimicrobial Resistance, commissioned by the UK Government, AMR could result in killing 10 million persons per year by 2050 unless immediate interventions are implemented. The World Health Organization (WHO) has declared that the world is heading toward a post-antibiotic era, where minor infections and injuries could once again be life-threatening owing to the widespread bacterial resistance to conventional antibiotics. Therefore, AMR must be addressed with great urgency.
Aside from acquiring antibiotic-resistance, bacteria can evade antibiotics by readily entering into a nongrowing, dormant state. Most antibiotics target biosynthetic processes, such as DNA, protein, and cell wall synthesis during bacterial growth. However, these targets are inactive in the dormant state, so that the metabolically inactive bacteria can maintain their viability under lethal antibiotic exposure. This ability to survive antibiotic exposure without any genetic modification is defined as antibiotic tolerance. The bacteria showing tolerance to multiple antibiotics are called persisters. Clinically, persisters are responsible for antibiotic tolerance of biofilms and recalcitrance of chronic infections. Currently there is no antibiotics effective against multi-drug resistant and/or persistent bacteria.
Lack of innovation in novel antibiotic development along with misuse/overuse of antibiotics poses an obstacle in addressing antibiotic resistance and tolerance. To overcome these two hurdles, it is imperative to develop innovative antibiotic pipelines and modalities to assist with rapid and precise determination of antibiotics prescribed to patients. We focus on three topics: discovering novel antibiotics using the Caenorhabditis elegans infection model, designing membrane-active antimicrobials against bacterial persisters, and developing rapid diagnostic strategies for antibiotic resistance.
Soo Min Kim, Guijin Zou, Hyerim Kim, Minjeong Kang, Soyeon Ahn, Hee Young Heo, Jae-Seok Kim, Kyung-Min Lim, Frederick M. Ausubel, Eleftherios Mylonakis, Huajian Gao, Wooseong Kim. Antimicrobial activity of the membrane-active compound nTZDpa is enhanced at low pH. Biomedicine & Pharmacotherapy 2022, 150, 112977
Wooseong Kim, Guijin Zou, Wen Pan, Nico Fricke, Hammad A. Faizi, Soo Min Kim, Rajamohammed Khader, Silei Li, Kiho Lee, Iliana Escorba, Petia M. Vlahovska, Huajian Gao, Frederick M. Ausubel, Eleftherios Mylonakis. The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant Staphylococcus aureus. mBio 2020 11(3): e01140-20
Wooseong Kim, Guijin Zou, Taylor P. A. Hari, Ingrid K. Wilt, Wenpeng Zhu, Nicolas Galle, Hammad Faizi, Gabriel Hendricks, Katerina Tori, Wen Pan, Xiaowen Huang, Andrew D. Steele, Erika E. Csatary, Madeline M. Dekarske, Jake L. Rosen, Noelly de Queiroz Ribeiro, Kiho Lee, Jenna Port, Beth Burgwyn Fuchs, Petia M. Vlahovska, William M. Wuest, Huajian Gao, Frederick M. Ausubel, Eleftherios Mylonakis. A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus. Proc. Natl. Acad. Sci. USA 2019, 116(33) 16529-16534.
Wooseong Kim, Andrew D. Steele, Wenpeng Zhu, Erika E. Csatary, Nico Fricke, Madeline M. Dekarske, ElamparithiJayamani, Wen Pan, Bumsup Kwon|, Isabelle F. Sinitsa, Jake L. Rosen, Annie L. Conery, Beth Burgwyn Fuchs, Petia M. Vlahovska, Frederick M. Ausubel, Huajian Gao, William M. Wuest, Eleftherios Mylonakis. Discovery and optimization of nTZDpa as an antibiotic effective against bacterial persisters. ACS Infectious Diseases. 2018, 4(11), 1540-1545.
Wooseong Kim, Wenpeng Zhu, Gabriel Lambert Hendricks, Daria Van Tyne, Andrew D. Steele, Colleen E. Keohane, Nico Fricke, Annie L. Conery, Steven Shen, Wen Pan, Kiho Lee, Rajmohan Rajamuthiah, Beth Burgwyn Fuchs, Petia M. Vlahovska, William M. Wuest, Michael S. Gilmore, Huajian Gao, Frederick M. Ausubel, Eleftherios Mylonakis. A new class of synthetic retinoid antibiotics effective against bacterial persisters. Nature. 2018, 556 (7699): 103-107.