Pyridine-containing iridium complexes as gram-negative bacteria specific therapeutic agents with low resistance...

Area of Science:

• Medicinal Chemistry
• Inorganic Chemistry
• Microbiology

Background:

• Antibiotic resistance and misuse pose significant challenges in antibacterial therapy.
• Low selectivity of current antibiotics contributes to resistance and misuse.
• Development of novel antibacterial agents with improved selectivity is crucial.

Purpose of the Study:

• To design and synthesize novel pyridine-modified iridium complexes as potential antibacterial agents.
• To evaluate the antibacterial activity and selectivity of these complexes against Gram-negative and Gram-positive bacteria.
• To investigate the mechanism of action and in vivo efficacy of the most promising complex.

Main Methods:

• Synthesis of three amphiphilic pyridine-modified iridium complexes: IrP, IrF, and Ir-X.
• Assessment of bactericidal activity against Gram-negative (E. coli, P. aeruginosa, A. baumannii) and Gram-positive (S. aureus, E. faecalis) bacteria.
• Evaluation of selective binding to Gram-negative pathogens.
• Mechanistic studies including membrane disruption, reactive oxygen species (ROS) generation, and ATP depletion assays.
• In vivo efficacy testing in a murine model of acute peritonitis.

Main Results:

• All synthesized iridium complexes demonstrated stronger bactericidal activity against Gram-negative bacteria compared to Gram-positive bacteria.
• The complexes exhibited selective binding to Gram-negative pathogens.
• Ir-X, with a logP of 2.58, showed the most promising antibacterial profile and efficacy.
• Mechanistic studies indicated that Ir-X kills E. coli via membrane disruption, ROS generation, and ATP depletion.
• In vivo experiments showed Ir-X effectively suppressed E. coli infection in mice with minimal tissue damage.

Conclusions:

• The designed pyridine-modified iridium complexes possess significant antibacterial activity, particularly against Gram-negative pathogens.
• Ir-X is identified as a potent therapeutic candidate due to its superior efficacy, selectivity, and favorable mechanism of action.
• Ir-X demonstrates potential for treating Gram-negative bacterial infections with minimal host tissue damage.