It is almost a cliché to say that antimicrobial resistance (AMR) poses a serious threat to the global public health. A case in point: infections with methicillin-resistant staphylococcus aureus (MRSA) were traditionally restricted to hospital settings. In recent years, community-associated MRSA strains have emerged with capacity of infecting otherwise healthy individuals. As the result, the morbidity and mortality of MRSA infections that are resistant to conventional antibiotics are on the rise for patients in both hospital and community settings. This dire situation is worsened by the slow rate of drug discovery and development to treat such infections. A strategy to develop new antibacterial compounds by means of modifying or adding a small chemical group to conventional antibiotics had limited success in disabling the development of drug resistance. There is such urgent need for a paradigm shift from the development of new antibiotics to that of rationally designed small-molecule antimicrobial agents with fundamentally different molecular targets than those of conventional antibiotics.
Our strategy to tackle this issue was to choose lawsone, a naturally occurring hydroxynaphthoquinone (i.e. 2-hydroxy-1,4-naphthoquinone), as the starting pharmacophoric platform for synthesizing new antimicrobial compounds. We have therefore developed a series of synthetic derivatives of lawsone by harnessing its characteristic to undergo the stepwise one-electron reduction to semiquinone, and then to hydroquinone. Such redox activity can mediate the reaction between NADH and molecular oxygen (O2) to produce intracellular reactive oxygen species (ROS) to exhibit antimicrobial activity. One of such derivatives, referred to as 6c in the article, with a para-butyl benzyl group attached to the 3-position of the lawsone ring could exhibit remarkable antimicrobial activity against MRSA. Its drug efficacy was comparable to that of conventional antibiotics, including vancomycin, with a resistance profile that surpasses them, which we believe, due mainly to the two structural characteristics that enable multifaceted mechanism of action. First, the naphthoquinone structural platform is not found in any class of clinical antibiotics or synthetic antimicrobial drugs. Second, the α-hydroxy ketone moiety renders lawsone a hard Lewis base and an excellent bidentate chelating agent selective for the Fe3+ ion in the presence of other bio-essential metal ions, which leads to the disruption of bacterial iron homeostasis. As the result, the molecular targets of 6c are so nascent that do not overlap with any known gene mutation pathways triggered by the existing drugs. Also noticeable is the introduction of the para-butyl benzyl pendant as a means of increasing the overall lipophilicity of 6c. This structural moiety is unknown to the current antibiotics or synthetic antimicrobial drugs, which presents a mysterious dilemma for the bacterial efflux pumps or enzymes to cope with. Together, these factors must have quickly overwhelmed the evolutionary response of bacteria to simultaneously mutate the genes to subdue the drug. This unique mode of action can be further explored for the treatment of multidrug-resistant infections as a new antibacterial strategy that can decrease the likelihood of bacterial resistance,.