An unanticipated discovery towards novel naphthalimide corbelled aminothiazoximes as potential anti-MRSA agents and allosteric modulators for PBP2a

Available therapeutic strategies are urgently needed to conquer multidrug resistance of MRSA. A visible effort was guided towards the advancement of novel antibacterial framework of naphthalimide corbelled aminothiazoximes, and desired to assert some insight on the conjunction of individual pharmacophore with distinct biological activities and unique action mechanism. Preliminary assessment displayed that dimethylenediamine derivative 13d presented a wonderful inhibition on MRSA (MIC = 0.5 μg/mL), and showed excellent membrane selectivity (HC50 > 200 μg/mL) from an electrostatic distinction of the electronegative bacterial membranes and the electroneutral mammalian membranes. Moreover, 13d could effectually relieve the development of MRSA resistance. Investigations into explaining the mechanism of anti-MRSA disclosed that 13d displayed strong lipase affinity, which facilitated its permeation into cell membrane, causing membrane depolarization, leakage of cytoplasmic contents and lactate dehydrogenase (LDH) inhibition. Meanwhile, 13d could exert interaction with DNA to hinder biological function of DNA, and disrupt the antioxidant defense system of MRSA through up-regulation of ROS subjected the strain to oxidative stress. In particular, the unanticipated mechanism for naphthalimide corbelled aminothiazoximes that 13d could suppress the expression of PBP2a by inducing allosteric modulation of PBP2a and triggering the open of the active site, was discovered for the first time. These findings of naphthalimide corbelled aminothiazoximes as a small-molecule class of anti-MRSA agents held promise in strategies for treatment of MRSA infections. A desirable family of unique naphthalimide corbelled aminothiazoximes as novel antibacterials were exploited. Experimental investigation with membrane destruction, inhibition of LDH, protein leakage, oxidative damage, DNA interaction and allosteric modulation of PBP2a suggested possible antibacterial mechanism. [Display omitted] •Novel naphthalimide corbelled aminothiazoximes as antibacterials were exploited.•Compound 13d possessed low toxicity, safe hemolysis level and no resistance.•Compound 13d presented lipase affinity and caused membrane disruption.•Compound 13d could destroy antioxidant defense system and lead to oxidative damage.•Compound 13d could bind to the allosteric site of PBP2a to resurrect older drugs.