Objective

The major classes of antibacterial agents used in systemic therapy (e.g. b-lactams, glycopeptides, macrolides, aminoglycosides, fluoroquinolones and tetracyclines) effectively multi-target and are not subject to high level single step mutation to resistance. This is important to bear in mind with the ever onward push to identify novel antibacterial targets that might be able to sidestep existing, typically transmissible, mechanisms of resistance. Furthermore, the frequency of spontaneous point mutation, the bacterial load being targeted, and the concentration of drug delivered to the site of infection and bacterial target, are all important factors in the probability of resistance emerging during single target (mono)therapy. This leaves discovery programs aiming at single targets vulnerable to the rapid emergence of resistance, unless, there is the potential to partner new drugs in combination therapy. The happy co-incidence of b-lactams and b-lactamase inhibitors having compatibility pharmacological profiles is a real success story, so it is possible, and combination therapy for HIV and TB is the norm. Here I'll discuss our current approaches to multi-target the 'old' and 'new'. Combining mechanistic understanding with structurally informed discovery, and HTS.