In the face of increasing bacterial resistance to all known antibiotics, efforts to discover new classes of antibiotics have languished, creating an urgent need to accelerate the antibiotic discovery pipeline. A major deterrent in the discovery of new antibiotics is the limited permeability of molecules across the bacterial envelope. Notably, the Gram-negative bacteria have nutrient specific protein channels (or porins) that restrict permeability of non-essential molecules including antibiotics. To accelerate the antibiotic discovery process, we have developed the ComputationaL Antibiotic Screening Platform (CLASP) for high-throughput screening of potential drug molecules through the porins. The CLASP takes advantage of coarse grain (CG) resolution, advanced sampling techniques, and a parallel computing environment to maximize its performance. The CLASP yields comprehensive thermodynamic and kinetic output data of a potential drug molecule within a few hours of wallclock time. Its output includes the potential of mean force profile, energy barrier, rate constant, half-life of the molecule’s transport process, contact analysis of the molecule with the pore-lining residues, and the orientational analysis of the molecule in the porin channel. In our first CLASP application, we report the transport properties of six carbapenem antibiotics—biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem—through OccD3, a major channel for carbapenem uptake in P. aeruginosa. The OccD3 channel is a nanopore with a constriction zone lined by a combination of polar and bulky nonpolar residues. These residues provide size selectivity to the porin and make small molecule uptake in P. aeruginosa cells much harder. The CLASP is designed to screen small molecule libraries with a fast turnaround time to yield structure-property relationships to discover antibiotics with high permeability. The CLASP will be freely distributed to enable accelerated antibiotic drug discovery.
