Infectious disease programs at MCCB
The infection caused by multi-drug resistant (MDR) bacteria has been a significant threat to the human healthcare. The situation is getting more dreadful due to the emergence of so-called "superbugs" that cannot be controlled by most of available antibiotic drugs. A recent report by Review on Antimicrobial Resistance (sponsored by Wellcome-Trust and UK government) estimated that the infection caused by MDR pathogens will be the number one cause of death in 2050 by reaching 10 million death worldwide (the second would be cancer, https://amr-review.org). Unfortunately, despite great endeavors by a lot of scientists worldwide over the last decades, only a handful of new antibiotic drugs have been introduced to the clinic, but superbugs are already beginning to develop resistance towards some of them. In this regard, development of a novel, groundbreaking strategy to tackle this infection problem is urgently called for. The MCCB laboratory has formulated a number of research projects to propose alternative therapeutic options to effectively treat the infections caused by superbugs.
Project #1. Antibiotic delivery system based on the siderophore metabolism
Researchers: Do Young Kim (김도영), Seung Woo Kim (김승우), Jiseok Oh (오지석)
The siderophore is a small molecule chelator that most bacteria including MDR pathogens employ to assimilate the iron from the environment. The siderophore metabolism consists of siderophore biosynthesis, siderophore export, extracellular iron capture by a siderophore, uptake of the iron-siderophore complex, and finally mobilization of a free iron from the complex inside the cell. Since the iron is an essential element for bacterial survival, most pathogens heavily rely on the siderophore metabolism for their survival in the human host.
Our antibiotic delivery strategy is based on delivery of an antibiotic warhead inside the cell via a siderophore uptake pathway by preparation and use of a siderophore-antibiotic conjugate. In many superbugs, particularly gram-negative pathogens including Acinetobacter baumannii and Pseudomonas aeruginosa, antibiotic resistance is conferred by reduced drug permeability in the outer membrane. Therefore, the siderophore-based antibiotic delivery strategy would be particularly effective in combating against those pathogens. Indeed, a recent FDA approval of cefiderocol, a siderophore-cephalosporin conjugate developed by Shionogi, well-demonstrates the efficaciousness of this approach. The MCCB laboratory is currently working on developing new antibiotic delivery systems that employ A. baumannii native siderophores to specifically target this deadly superbug.
Project #2. Invigoration of legacy antibiotics via discovery of a novel adjuvant
Researchers: Seung Woo Kim (김승우), Jiseok Oh (오지석)
The term "adjuvant" is used to refer to a molecule capable of boosting the effect of a certain pharmacological agent when used together. Recently, in collaboration with researchers at Kyungpook National University School of Medicine, we have discovered a novel adjuvant compound that shows dramatic synergism upon co-treatment with aminoglycoside antibiotics against MDR A. baumannii. Currently, the MCCB laboratory is working on structural optimization to derive a potent lead compound as well as on identification of its cellular target to elucidate the pharmacological mechanism.
Edited in Feb, 2023