RecA is a ubiquitous bacterial protein whose sequence is highly conserved across all bacteria.  RecA’s structure, functions, and mechanisms of action have been studied over 40 years, with its role in the development of bacterial resistance having been elucidated over the past six years.

The bacterial SOS response is an important inducible gene network whose products collaborate in promoting survival from antibiotic killing as well as in producing resistance-conferring mutations. RecA functions in upregulating SOS response genes and directly participates in SOS repair by restarting stalled replication forks through recombinational DNA repair. These functions of RecA have been studied in a number of organisms, including the pathogens  Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacillus subtilis (as a surrogate for B. anthracis), Neisseria gonorrhoeae, Neisseria meningitids, Streptococcus pneumoniae, and Mycobacterium tuberculosis.

It is well established that RecA mediates the abilities of bacteria such as E. coli, P. aeruginosa, and S. aureus to overcome the metabolic stress induced by a range of antibacterial agents. Although these phenomena have been acknowledged to reflect RecA’s roles in SOS induction and recombinational DNA repair, the link between varied antibacterials with different mechanisms of action and DNA damage was not established until recently. Work in the laboratory of Synereca SAB member Jim Collins revealed that the RecA-activated SOS response specifically enhnaces the bacteria’s survival of antibacterial-induced free radicals. Bacterial strains lacking RecA function are highly sensitized to antibacterial agents (i.e., minimum inhibitory concentrations (MIC) are reduced ≥ 10-fold). Moreover, mice infected with E. coli having suppressed SOS networks survive the infection significantly more frequently than mice infected by unsuppressed bacteria. Taken together, these results strongly suggest that a cell-permeable small molecule that inhibits RecA could act as a strong adjuvant for traditional antibacterial chemotherapies by increasing the therapeutic index.

Synereca’s discovery program has identified prototypical RecA inhibitors that potentiate the killing of E. coli by a number of conventional antibacterial agents, resulting in the following significant changes: increased fraction of a bacterial population that is killed by a given dose of an antibacterial; reduced dose of an antibacterial required to achieve a targeted killing rate; and reduced MIC.  Further preliminary results suggest that the prototypic RecA inhibitors are effective against a number of pathogenic bacteria, including those responsible for lung, urinary tract, and skin infections, as well as weaponizable Gram-positive and Gram-negative pathogens.