Lipophilic Ga Complex with Broad-Spectrum Antimicrobial Activity and the Ability to Overcome Gallium Resistance in both Pseudomonas aeruginosa and Staphylococcus aureus.

Lipophilic Ga Complex with Broad-Spectrum Antimicrobial Activity and the Ability to Overcome Gallium Resistance in both Pseudomonas aeruginosa and Staphylococcus aureus.

Wang Z; Li J; Benin BM;Yu B; Bunge Scott D; Abeydeera N; Huang SD; Kim M-H

Journal Of Medicinal Chemistry

2021

2021-06-17

Antibiotic resistance (AR) necessitates the discovery of new antimicrobials with alternative mechanisms of action to those employed by conventional antibiotics. One such strategy utilizes Ga3+ to target iron metabolism, a critical process for survival. Still, Ga-based therapies are generally ineffective against Gram-positive bacteria and promote Ga resistance. In response to these drawbacks, we report a lipophilic Ga complex, [Ga2L3(bpy)2] (L = 2,2′-bis(3-hydroxy-1,4-naphthoquinone; bpy = 2,2′-bipyridine)), effective against drug-resistant Pseudomonas aeruginosa (DRPA; minimum inhibitory concentration, MIC = 10 μM = 14.8 μg/mL) and methicillin-resistant Staphylococcus aureus (MRSA, MIC = 100 μM = 148 μg/mL) without iron-limited conditions. Importantly, [Ga2L3(bpy)2] shows noticeably delayed and decreased resistance in both MRSA and DRPA, with only 8× MIC in DRPA and none in MRSA after 30 passages. This is likely due to the dual mode of action afforded by Ga (disruption of iron metabolism) and the ligand (reactive oxygen species production). Overall, [Ga2L3(bpy)2] demonstrates the utility of lipophilic metal complexes with multiple modes of action in combatting AR in Gram-positive and Gram-negative bacteria.

In recent years, drug-resistant pathogenic bacteria have spread faster than the discovery of new antibiotics. (1,2) It is estimated that more than 30% of clinical isolates of Pseudomonas aeruginosa (P. aeruginosa) from patients in any given intensive care unit or nursing home are now resistant to three or more antibiotic drugs. (3) This situation is very similar for other pathogenic organisms as well. (4) Currently, very few new antibiotics are in an advanced development stage as a result of fewer large, pharmaceutical companies engaging in antibiotic research and the fact that the successful use of soil-derived antibiotics has, after over 70 years of intensive screening, often resulted in repeated isolation of known compounds. (5) This dire situation has resulted in an increased rate of morbidity and mortality stemming from bacterial infections. (6) In the era of antibiotic resistance, a paradigm shift from the development of new antibiotics via structural modifications to nonconventional antimicrobial alternatives is warranted.

Journal Article

NEOMED College of Medicine

Department of Integrative Medical Sciences

Jan to Aug list 2021