When pathogens developed beta-lactamases (classes A, B, C and D) to hydrolyse and counter the action of beta-lactams, beta-lactamase inhibitors (class A) were developed to be used in combination with beta-lactams. Several studies have been carried out to identify new series of PBP and beta-lactamase inhibitors, though few have been successful. The most prominent discovery is certainly the DBO series discovered by Aventis in the late 90s.
Gram-negative bacteria, due to their double membrane and efflux pumps, are the bacteria against which it is most difficult to develop antibiotics. These bacteria are those that today show the most worrying resistance; some of which resist all front-line antibiotic treatments.
Beta-lactams are a large family of antibiotics that include, amongst others, penicillins, cephalosporins and carbapenems, and target PBPs (penicillin-binding proteins). It represents 65% of the antibiotics sold throughout the world and a large part of research efforts in the past decades.
Dabocins are DBO derivatives that specifically target PBP, like b-lactams. These new antibiotics have an essential advantage over b-lactams: they are impervious to the resistance induced by b-lactamases. Dabocins are active against gram-negative bacteria, including carbapenem-resistant Enterobacteriaceae (CRE) and potentially P. aeruginosa. These compounds are bactericides, present very a low frequency of resistance, and are active in vivo. The targeted profile is intravenous treatment of hospital infections caused by gram-negative bacteria.
These b-lactamase inhibitors, also DBO derivatives, present excellent oral bioavailability compared to those previous. In combination with oral cephalosporin, they mainly target the treatment of urinary infections caused by the Enterobacteriaceae producing ESBLs and KPC and OXA-48 type carbapenemases.