Quantum biochemical analysis of the TtgR regulator and effectors

Abstract

The recent expansion of multidrug-resistant (MDR) pathogens poses significant challenges in treating healthcare-associated infections. Although antibacterial resistance occurs by numerous mechanisms, active efflux of the drugs is a critical concern. A single species of efflux pump can produce a simultaneous resistance to several drugs. One of the best-studied efflux pumps is the TtgABC: a tripartite resistance-nodulation-division (RND) efflux pump implicated in the intrinsic antibiotic resistance in Pseudomonas putida DOT-T1E. The expression of the TtgABC gene is down-regulated by the HTH-type transcriptional repressor TtgR. In this context, by employing quantum chemistry methods based on the Density Functional Theory (DFT) within the Molecular Fragmentation with Conjugate Caps (MFCC) approach, we investigate the coupling profiles of the transcriptional regulator TtgR in complex with quercetin (QUE), a natural polyphenolic flavonoid, tetracycline (TAC), and chloramphenicol (CLM), two broad-spectrum antimicrobial agents. Our quantum biochemical computational results show the: [i] convergence radius, [ii] total binding energy, [iii] relevance (energetically) of the ligands regions, and [iv] most relevant amino acids residues of the TtgR-QUE/TAC/CLM complexes, pointing out distinctions and similarities among them. These findings improve the understanding of the binding mechanism of effectors and facilitate the development of new chemicals targeting TtgR, helping in the battle against the rise of resistance to antimicrobial drugs. These advances are crucial in the ongoing fight against rising antimicrobial drug resistance, providing hope for a future where healthcare-associated infections can be more beneficially treated.

Adsorption of Flavonoids in a Transcriptional Regulator TtgR: Relative Binding Free Energies and Intermolecular Interactions

“…Complementary to experimental investigations, the TtgR transcriptional regulator has garnered considerable attention in computational studies. − Recently, Zhang and co-workers performed equilibrium and nonequilibrium free energy simulations to predict the binding thermodynamics of TtgR toward a series of organic molecules and drugs, and examined the dynamics of the resulting protein–ligand complexes . Considering the significant antimicrobial potential of flavonoids, in this work, we focus on seven such compounds and their derivatives and utilize a combination of molecular dynamics (MD) and alchemical free energy (AFE) simulations to explore their binding free energies and modes of interactions with the TtgR transcriptional regulator.…”