The challenge of converting Gram‐positive‐only compounds into broad‐spectrum antibiotics

Abstract

Multidrug resistant Gram-negative bacterial infections are on the rise, and there is a lack of new classes of drugs to treat these pathogens. This drug shortage is largely due to the challenge of finding antibiotics that can permeate and persist inside Gram-negative species. Efforts to understand the molecular properties that enable certain compounds to accumulate in Gram-negative bacteria based on retrospective studies of known antibiotics have not been generally actionable in the development of new antibiotics. A recent assessment of the ability of >180 diverse small molecules to accumulate in Escherichia coli led to predictive guidelines for compound accumulation in E. coli. These "eNTRy rules" state that compounds are most likely to accumulate if they contain a nonsterically encumbered ionizable Nitrogen (primary amines are the best), have low Three-dimensionality (globularity ≤ 0.25), and are relatively Rigid (rotatable bonds ≤ 5). In this review, we look back through 50+ years of antibacterial research and 1000s of derivatives and assess this historical data set through the lens of these predictive guidelines. The results are consistent with the eNTRy rules, suggesting that the eNTRy rules may provide an actionable and general roadmap for the conversion of Gram-positive-only compounds into broad-spectrum antibiotics.

Probing for Thiol‐Mediated Uptake into Bacteria

“…In bacteria, there is much interest in mechanistically new delivery strategies. Potential antibiotics often fail because of their inability to reach their target . This is particularly true for Gram‐negative bacteria.…”

“…Ampicillin ( 3 ) is a β‐lactam antibiotic that inhibits cell wall synthesis by binding to cytosolic or membrane‐bound penicillin‐binding proteins (PBP) . It is active against Gram‐negative strains as the primary amine permits its passage through counterion‐gated porins in the OM.…”

Empowering Synthesis of Complex Natural Products

“…However, the development of new classes of antibiotics has proven challenging, and microbial resistance to last‐resort antibiotics has evolved faster than new treatments could be discovered. Recently, there has been a renaissance in the treatment of these MDR gram‐negative pathogens by the conversion of gram‐positive‐only antibiotics to broad spectrum compounds through the discovery and employment of the “eNTRy” rules . In 2014, Baran and Romesberg revealed that pyrrole–imidazole alkaloids (PIAs), in particular axinellamines A and B ( 1 and 2 , respectively), were a potent class of compounds across multiple gram‐positive and gram‐negative strains .…”

Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise

“…[52] Wissenschaftler haben daher in Anlehnung an Lipinskis Rule of Five füroral verfügbare Wirkstoffe versucht, Leitfäden füre ine gute bakterielle Penetration aufzustellen. [59,60] In der Zwischenzeit sind die Limitierungen heutiger Substanzbibliotheken gut verstanden, und zeitgemäße Ansätze zielen darauf,den chemischen Raum fürantibakterielle Screenings zu vergrçßern. [56][57][58] Im Rahmen einer umfangreichen Studie quantifizierte die Gruppe um Hergenrother mittels Massenspektrometrie die Akkumulation von über 180 Substanzen innerhalb von Escherichia coli und korrelierte zu diesen Daten die jeweiligen physikochemischen Eigenschaften.…”