Fig. 2: The figure illustrates the physicochemical parameters of compounds studied to overcome the outer membrane barrier of Gram-negative bacteria.

Of these rules, traditional drug space of orally bioavailable compounds (Lipinski rules) suggests that a druggable molecule should possess an av. mol. wt. of <500 Da, with <5 hydrogen bond donors, ≤10 hydrogen bond acceptors and calculated octanol-water partition coefficient (clogP ≤ 5). These physicochemical properties were further narrowed down by O’Shea and Moser’s, according to which, a Gram-negative targeting compound must possess an average mol. wt. of 414 Da with clogP ~ 0.1. Later, according to the eNTRy rules proposed by Hergenrother and colleagues, compounds with ionizable nitrogen, globularity ≤0.25 and rotational bond ≤5 are more likely to accumulate in Gram negatives. Glob globularity, RB number of rotatable bonds. Figure created with BioRender.com.