Adjuvant Activity and Resistance-Modifying Capacity of a Novel Heterocyclic Hydrazone Derived from the Drug Hydralazine in NorA and MepA Efflux Pumps of Staphylococcus aureus

Background/Objectives: Hydrazones are organic compounds with the general structure R2C=NNHR1, distinguished by their versatility and modifiability, and are widely used in various applications due to their physicochemical and biological properties. They exhibit anticancer, anti-inflammatory, antibiofilm, and antibacterial activities. Antibiotic-resistant bacteria pose a serious public health threat, employing mechanisms such as enzymatic inactivation and efflux pumps. This study evaluated the antibacterial activity of the hydrazone HDZH1,4BENZ, a hydralazine-derived compound, as well as its potential adjuvant effect in combination with antibiotics against Staphylococcus aureus strains expressing efflux pumps. Methods: The strains used were 1199B (NorA efflux pump-expressing) and K2068 (MepA efflux pump-expressing). All assays were conducted using the broth microdilution method in Brain Heart Infusion (BHI) medium. Initially, the intrinsic antibacterial activity of the compound was determined. Subsequently, modulation assays were performed to evaluate its potential effect on efflux pump activity, with a standard efflux pump inhibitor included as a positive control. Results: Although HDZH1,4BENZ did not demonstrate significant direct antibacterial activity, the results indicate that this hydrazone exerts a notable inhibitory effect on the NorA (Norfloxacin resistance efflux pump A) and MepA (Multidrug efflux protein A) efflux pumps in S. aureus, thereby enhancing the efficacy of antibacterial agents. Conclusions: The activity of the hydrazone was comparable to that of chlorpromazine, suggesting that it may represent a promising alternative in the fight against antibiotic-resistant bacterial infections.