The rise of multidrug-resistant Gram-negative bacteria is a serious threat to public health. To combat these dangerous pathogens, we urgently need new antibiotics that work differently than existing ones. One promising approach is to target lipid A biosynthesis, a critical process for maintaining the integrity of the bacterial cell wall and bacterial survival.
Researchers in the Hong Lab, in collaboration with the Zhou (Department of Biochemistry) and Yang (Department of Chemistry) Labs, have developed promising candidate compounds for new antibiotics to combat drug-resistant Gram-negative bacteria. These new compounds, JH-LPH-106 and JH-LPH-107, target the bacterial enzyme LpxH in the lipid A biosynthesis pathway. Lipid A biosynthesis is essential for maintaining the integrity of the bacterial cell wall. By inhibiting LpxH, these compounds not only disrupt lipid A biosynthesis, but they cause a buildup of toxic substances within the bacteria, ultimately leading to bacterial killing. Both JH-LPH-106 and JH-LPH-107 have shown potent activity against wild-type Enterobacterales such as like Escherichia coli and Klebsiella pneumoniae while exhibiting a low rate of spontaneous resistance and a high safety window in vitro. This breakthrough represents a significant step forward in addressing the urgent need for new antibiotics to combat the growing threat of drug-resistant infections. Read more about their work, “Design and Evaluation of Pyridinyl Sulfonyl Piperazine LpxH Inhibitors with Potent Antibiotic Activity Against Enterobacterales” in a recent JACS Au article here.
