Gallium Porphyrin and Gallium Nitrate Synergistically Inhibit Mycobacterial Species by Targeting Different Aspects of Iron/Heme Metabolism
| Autor: | Prabagaran Narayanasamy, Bradley E. Britigan, Barb Switzer, Seoung Ryoung Choi |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Gallium nitrate biology 030106 microbiology Mycobacterium abscessus biology.organism_classification Aconitase Microbiology Mycobacterium tuberculosis 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology Infectious Diseases Enzyme chemistry Catalase medicine biology.protein Heme medicine.drug Mycobacterium |
| Zdroj: | ACS Infectious Diseases. 6:2582-2591 |
| ISSN: | 2373-8227 |
| DOI: | 10.1021/acsinfecdis.0c00113 |
| Popis: | There is an urgent need for new effective and safe antibiotics active against pathogenic mycobacterial species. Gallium (Ga) nitrate (Ga(NO3)3) and Ga porphyrin (GaPP) have each been shown to inhibit the growth of a variety of mycobacterial species. The Ga(III) ion derived from Ga(NO3)3 has the potential to disrupt the mycobacterial Fe(III) uptake mechanisms and utilization, including replacing iron (Fe) in the active site of enzymes, resulting in the disruption of function. Similarly, noniron metalloporphyrins such as heme mimetics, which can be transported across the bacterial membrane via heme-uptake pathways, would potentially block the acquisition of iron-containing heme and bind to heme-utilizing proteins, making them nonfunctional. Given that they likely act on different aspects of mycobacterial Fe metabolism, the efficacy of combining Ga(NO3)3 and GaPP was studied in vitro against Mycobacterium avium, Mycobacterium abscessus, and Mycobacterium tuberculosis (M. tb). The combination was then assessed in vivo in a murine pulmonary infection model of M. abscessus. We observed that Ga(NO3)3 in combination with GaPP exhibited synergistic inhibitory activity against the growth of M. avium, M. tb, and M. abscessus, being most active against M. abscessus. Activity assays indicated that Ga(NO3)3 and GaPP inhibited both catalase and aconitase at high concentrations. However, the combination showed a synergistic effect on the aconitase activity of M. abscessus. The Ga(NO3)3/GaPP combination via intranasal administration showed significant antimicrobial activity in mice infected with M. abscessus. M. abscessus CFU from the lungs of the Ga(NO3)3/GaPP-treated mice was significantly less compared to that of nontreated or single Ga(III)-treated mice. These findings suggest that combinations of different Ga(III) compounds can synergistically target multiple iron/heme-utilizing mycobacterial enzymes. The results support the potential of combination Ga therapy for development against mycobacterial pathogens. |
| Databáze: | OpenAIRE |
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