Towards a Single Model for Antibiotics against Gram-Negative Bacteria

The discovery of novel antibiotics against Gram-negative bacteria is hampered by their highly effective defense mechanism these bacteria developed. These defense mechanism consists of a barrier of two membranes, preventing small molecules to penetrate, and of efficient efflux pump systems, removing any small molecule which succeeded in penetrating the two membranes. These mechanisms have been identified as main reason of failure of many antibiotic discovery efforts. Here we review and combine different approaches that investigated how small molecules penetrate the membranes and accumulate inside Gram-negative bacteria. Despite different approaches, common physicochemical properties have been identified, which overlap with earlier retrospective analysis of existing antibiotics. In general, the electrostatic property is the most significant property in each of the studies, with charged, polar molecules, or molecules with dipole moment, able to better penetrate and accumulate inside Gram-negative bacteria. In addition, the size of molecules displayed a limiting effect in most studies, with smaller molecules able to better penetrate the bacterial membrane. The combination of these studies confirm in general the current guidelines for a good model for Gram-negative antibiotics, while providing more detailed information on mechanism and variation between species.