Using permeation guidelines to design new antibiotics—A PASsagE into Pseudomonas aeruginosa

• Published in: Clinical and translational medicine Vol. 14; no. 3; pp. e1600 - n/a
• Main Authors: Cain, Brett N., Hergenrother, Paul J.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.03.2024; Wiley
• Subjects: Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotics; Bacteria; Bacterial infections; Drug resistance; E coli; Flexibility; Gram-negative bacteria; Humans; Hydrogen bonds; Nitrogen; Pathogens; Permeability; Pseudomonas aeruginosa; Pseudomonas Infections - drug therapy; Toxicity
• ISSN: 2001-1326; 2001-1326
• DOI: 10.1002/ctm2.1600

In addition to more typical drug-like small molecules, the collection contained novel, natural-product-like compounds constructed via the “complexity-to-diversity” approach.11 After experimentally measuring individual accumulation values for 345 compounds, the resulting data were interpreted with the help of a random forest classification model that pointed to certain characteristics associated with positive charge and hydrogen bond donation as important for P. aeruginosa accumulation. In brief, the 2017 study found that the presence of an ionizable nitrogen on a compound with low three-dimensionality and high rigidity enabled accumulation in E. coli.12 The spatial characteristics of rigidity and globularity are important for traversing the narrow porin channel constriction zone, which ranges from approximately 7 to 11 angstroms.14 The critical presence of an ionizable nitrogen has been traced to its ability to engage in favourable electrostatic interactions with negatively-charged amino acids that line the porin constriction zone.12,15–17 The P. aeruginosa permeation guidelines9—dubbed here the PASsagE rules (Pseudomonas aeruginosa Self-promoted Entry)—in contrast provide guidance for tailoring small molecules to productively access the self-promoted uptake pathway for entry into the cell, consistent with recent work from the Bumann lab suggesting that porins are not important for antibiotic uptake in P. aeruginosa.18 Notably, and in contrast with the eNTRy rules, the PASsagE rules have no flexibility and shape requirements, and instead appear to optimize favourable interactions of the small molecule with the gram-negative outer membrane through sufficient positive polar charge and HBDSA. The futility of whole-cell screening of industrial-style compound collections against gram-negative bacteria has been well-documented.36–38 The reasons behind this are not a mystery, as the large compound screening collections used by most research groups (academia and pharmaceutical industry) lack members with traits enabling gram-negative cell penetration; for example, only .1% of compounds in the Chembridge Microformat Library possess a primary amine.39 As compounds predisposed to penetrate gram-negative bacteria are not present in standard screening collections, turning to other sources for novel chemical matter makes sense with recent successes in discovering interesting antibacterial leads through mining “unculturable” bacteria,40 examining natural products produced by eukaryotic symbionts,41 and using non-standard chemical matter.42 A complimentary approach is chemically modifying a non-permeable antibiotic with functional groups that enhance accumulation; accumulation rules will guide such modifications and facilitate development of potent antibiotics.