Compound Uptake into E. coli Can Be Facilitated by N -Alkyl Guanidiniums and Pyridiniums
Year: 2020
Type: article
Abstract: Multidrug-resistant Gram-negative bacterial infections are on the rise, and with no FDA approvals for new classes of broad-spectrum antibiotics in over 50 years, these infections constitute a major threat to human health. A significant challenge is the inability of most compounds to accumulate in Gram-negative bacteria. Recently developed predictive guidelines show that appending a primary amine to an appropriately shaped compound can enhance Gram-negative accumulation. Here, we report that other positively charged nitrogen functional groups, namely, N -alkyl guanidiniums and pyridiniums, can also facilitate compound uptake into Gram-negative bacteria. The accumulation of a set of 60 nonantibiotic compounds, consisting of 20 primary amines and their corresponding guanidiniums and pyridiniums, was assessed in Escherichia coli . We also installed these alternate functional groups onto antibiotic scaffolds and assessed their accumulation and antibacterial activity in Gram-negative bacteria. The results suggest that other positively-charged, nitrogen-containing functional groups should be considered when designing antibiotics with Gram-negative activity.
Source: ACS Infectious Diseases
Language: English
Subfield: Molecular Medicine
Domain: Life Sciences
Open Access status: green
Awards: Defining Parameters for Compound Accumulation in Gram-Negative Pathogens, G2998649276, Development of a Novel Class of Gram-Negative Antibiotics that Target Bacterial RNA, G4963228974, G5663623749, Predictive Guidelines for Penetrance and Discovery of Broad-Spectrum Antibiotics, G7213724552, Training Program at the Chemistry Biology Interface
OpenAlex ID: W3109748344