Touya Toyomoto: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Katsuhiko Ono: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Tomoo Shiba: Department of Applied Biology, Graduate School of Science and Technology, Kyoto Institute of Technology, Kyoto, Japan.
Kenta Momitani: Department of Applied Biology, Graduate School of Science and Technology, Kyoto Institute of Technology, Kyoto, Japan.
Tianli Zhang: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Hiroyasu Tsutsuki: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Takeshi Ishikawa: Department of Chemistry, Biotechnology, and Chemical Engineering, Graduate School of Science and Engineering, Kagoshima University, Kagoshima, Japan.
Kanae Hoso: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Koma Hamada: Faculty of Advanced Science and Technology, Kumamoto University, Kumamoto, Japan.
Azizur Rahman: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Liping Wen: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Yosuke Maeda: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Keiichi Yamamoto: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Masao Matsuoka: Department of Hematology, Rheumatology, and Infectious Diseases, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Kenjiro Hanaoka: Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan.
Takuro Niidome: Faculty of Advanced Science and Technology, Kumamoto University, Kumamoto, Japan.
Takaaki Akaike: Department of Environmental Medicine and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Tomohiro Sawa: Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
A principal concept in developing antibacterial agents with selective toxicity is blocking metabolic pathways that are critical for bacterial growth but that mammalian cells lack. Serine -acetyltransferase (CysE) is an enzyme in many bacteria that catalyzes the first step in l-cysteine biosynthesis by transferring an acetyl group from acetyl coenzyme A (acetyl-CoA) to l-serine to form -acetylserine. Because mammalian cells lack this l-cysteine biosynthesis pathway, developing an inhibitor of CysE has been thought to be a way to establish a new class of antibacterial agents. Here, we demonstrated that alkyl gallates such as octyl gallate (OGA) could act as potent CysE inhibitors and in bacteria. Mass spectrometry analyses indicated that OGA treatment markedly reduced intrabacterial levels of l-cysteine and its metabolites including glutathione and glutathione persulfide in to a level similar to that found in lacking the gene. Consistent with the reduction of those antioxidant molecules in bacteria, became vulnerable to hydrogen peroxide-mediated bacterial killing in the presence of OGA. More important, OGA treatment intensified susceptibilities of metallo-β-lactamase-expressing Gram-negative bacteria ( and ) to carbapenem. Structural analyses showed that alkyl gallate bound to the binding site for acetyl-CoA that limits access of acetyl-CoA to the active site. Our data thus suggest that CysE inhibitors may be used to treat infectious diseases caused by drug-resistant Gram-negative bacteria not only via direct antibacterial activity but also by enhancing therapeutic potentials of existing antibiotics.
