Antibiotics | STOP Strategy Inhibits Growth of Plasmodium falciparum and Staphylococcus aureus: Study on Molecular Mechanisms

This study designed novel hybrid compounds using the STOP strategy targeting the NDH-2 enzyme, simultaneously inhibiting the growth of Plasmodium falciparum and Staphylococcus aureus. The compounds demonstrated strong antimicrobial and anti-malarial activity with low toxicity, offering new insights for the development of broad-spectrum anti-infective agents.

 

Literature Overview
This paper, 'STOP Strategy to Inhibit P. falciparum and S. aureus Growth: Molecular Mechanism Studies on Purposely Designed Hybrids' published in the journal Antibiotics, reviews and summarizes the design of novel hybrid compounds using the STOP strategy to simultaneously inhibit the growth of Plasmodium falciparum and Staphylococcus aureus. This study aims to address the growing problem of drug resistance in anti-infective agents by exploring new molecular targets and mechanisms to develop compounds with dual antimicrobial and anti-malarial activity.

Background Knowledge
Malaria is among the most severe parasitic diseases globally, causing over 600,000 deaths annually, particularly in sub-Saharan Africa. Co-infection with Plasmodium falciparum and Staphylococcus aureus is common among children with severe malaria. With increasing drug resistance, the development of new therapeutics is challenging. NDH-2 (NADH dehydrogenase II) is a key enzyme present in Plasmodium falciparum and Staphylococcus aureus but absent in mammals. It plays a crucial role in electron transport and maintaining the redox balance of NADH/NAD+. Thus, it is an ideal target for anti-infective drug development. By employing molecular docking, molecular dynamics simulations, and experimental validation, this study explores the dual activity of novel quinolone-phenothiazine hybrid compounds, providing a new chemical scaffold for anti-infective drug development.

 

 

Research Methods and Experiments
Researchers chemically synthesized a series of hybrid compounds by linking the pharmacophore of chloroquine, an anti-malarial drug, with the phenothiazine nucleus via various linkers. These compounds were tested in vitro for their inhibitory activity against Plasmodium falciparum and Staphylococcus aureus. Molecular docking and molecular dynamics (MD) simulations were used to analyze their interactions with the NDH-2 enzyme. In addition, their cytotoxicity against mammalian cells was assessed to determine the selectivity index (SI).

Key Conclusions and Perspectives

• Compounds 4b and 5b exhibited the best dual inhibitory activity, with IC50 values of 0.156 µM and 0.135 µM against Plasmodium falciparum, and MIC values of 4.86 µM and 5.03 µM against Staphylococcus aureus.
• These compounds showed low cytotoxicity to mammalian cells in vitro, with favorable selectivity indices, indicating high safety.
• Molecular docking and MD simulations revealed that these compounds primarily bind to the coenzyme Q-binding pocket of NDH-2, forming hydrogen bonds, π–π stacking, and halogen bond interactions with key residues.
• The introduction of chlorinated phenothiazine structures significantly enhanced antimicrobial activity, highlighting the importance of this substituent in binding and inhibition.
• Compound 6b showed reduced activity due to its longer linker, suggesting that linker length significantly affects antimicrobial activity.
• All quinoline–phenothiazine hybrid compounds demonstrated nanomolar anti-malarial activity and showed similar IC50 values against the chloroquine-resistant W2 strain and the D10 strain, indicating a mechanism distinct from chloroquine and the absence of cross-resistance.

Research Significance and Prospects
This study provides a new chemical strategy for the simultaneous treatment of malaria and bacterial co-infections by targeting NDH-2, avoiding mammalian toxicity. Future work could focus on optimizing these compounds, enhancing their pharmacokinetic properties, evaluating their efficacy in animal models, and extending this strategy to dual targeting of other pathogens.

 

 

Conclusion
This study successfully designed and validated quinoline–phenothiazine hybrid compounds with dual antimicrobial and anti-malarial activity. Notably, compounds 4b and 5b demonstrated submicromolar inhibitory activity without significant cytotoxicity. Molecular mechanism analysis revealed that the target of these compounds is NDH-2, and although their binding modes differ between the two pathogens, they share a common binding pocket. This research lays the foundation for structural optimization and mechanistic studies in developing novel anti-infective drugs and opens new avenues for the treatment of multiple infections.

 

Beatrice Gianibbi, Riccardo Corina, Nicoletta Basilico, Francesca Bonvicini, and Alessandra Bisi. STOP Strategy to Inhibit P. falciparum and S. aureus Growth: Molecular Mechanism Studies on Purposely Designed Hybrids. Antibiotics.