Figure 1.

The chemical space conundrum. It is already difficult to identify chemicals that permeate bacterial outer envelopes. While recent work [27,28,29,30,31,32,33,34,35,36,37] has identified plausible characteristics enabling penetration of a few Gram-negative cells, Gram-positive permeability rules are virtually undiscovered. Additionally, only a fraction of chemicals capable of permeating the human cell can penetrate the bacterial cell to reach the cytosol. Chemicals that target intracellular bacteria must penetrate both (Substance A). Substance A must be both, Ro5-compliant, as well as bacterial cell-penetrating, which are difficult to find. Substance B, on the other hand, is useless against intracellular pathogens because it penetrates human cells but fails to reach bacterial targets. Substance C would be useless because it would not penetrate the human cell, even if it was able to reach the bacterial cytoplasm.