Quantum-chemical calculation, antibiotic potentiating activity, evaluation of efflux pump inhibition against S. aureus multi-resistant strains and molecular docking of the drugs isoniazid and hydralazine

Abstract

In recent years, due to the uncontrolled use of antibiotics and natural evolution, many pathogenic microorganisms have acquired resistance to currently available drugs. Consequently, the number of infections caused by these microorganisms, considered multi-resistant to antimicrobial drugs, has increased, becoming a serious global public health problem. In the search for alternative therapies, drug repositioning represents a promising way to introduce new medicines. Hydralazine exhibits antihypertensive and peripheral vasodilatory action and isoniazid is a prodrug used as the first choice for the chemotherapy treatment of tuberculosis. In this work, microbiological tests were performed to investigate the modulator potential and efflux pump inhibition on S. aureus multi-resistant strains of the drugs isoniazid and hydralazine. In addition, the Density Functional Theory was used to determine the electronic and reactivity properties. Association of Ciprofloxacin with hydralazine on the K2068 strain proved to be better than the association of Norfloxacin with this antihypertensive on the 1199B strain of S. aureus. Association of isoniazid with ciprofloxacin in the K2068 strain was irrelevant and may have generated antagonism. The opposite effect was observed when associated with Norfloxacin in strain 1199B, where a significant reduction in the MIC of Norfloxacin was observed when associated with isoniazid. Regarding the association of hydralazine and isoniazid with EtBr, the results of this study showed that only hydralazine was able to positively modify the MIC of bromide on strains 1199B and K2068, presenting better results with this last strain, while in tests with to isoniazid. Molecular docking was used to verify the feasibility of forming receptor-ligand complexes and the replicability of the results. The molecular docking study against MepA indicated a possible synergistic effect between hydralazine and the antibiotic ciprofloxacin. Regarding NorA, the data indicated that hydralazine could act through competitive inhibition with the control norfloxacin, since it interacts in the same region of the antibiotic binding site through interactions in common with residues Glu-222, Tyr-225 and Val -302.