The challenge of antimicrobial resistance is well understood and extensive research is underway worldwide to find effective, new antibacterial agents that will be less susceptible to the emergence of resistance than those of previous generations. The challenge of combining potency with resilience is unlikely to be met using the standard medicinal chemistry paradigm of single drug, single target, single effect. Our approach using specially designed minor groove binders for DNA (Strathclyde MGBs), whilst formally attacking a single molecular target, in practice disrupts many biological processes such that the emergence of resistance can be expected to be low. The first example of this approach to reach the clinic, MGB-BP-3, is highly effective against Gram positive bacteria and has been successfully taken through a Phase 1 clinical trial for the treatment of Clostridium difficile infections by our development partner, MGB Biopharma. Mechanism of action studies with S. aureus as the target organism have provided evidence consistent with the expectation. RNAseq experiments have shown that there are substantial changes in gene expression, some upregulated and others downregulated, such that the bacterium faces multiple metabolic challenges to its survival. In particular processes associated with cell wall integrity and energy production are affected, the latter being consistent with the steep dose response kill curve observed with this type of drug. Moreover attempts to generate resistant strains have failed. Taken together, these properties identify Strathclyde minor groove binders as significant new compounds in the fight against antibacterial resistance.