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Repurposing Non-Antibiotic Drugs Auranofin and Pentamidine in Combination to Combat Multidrug-Resistant Gram-Negative
Yingxiao Yu1, Huimin Zhao1, Jiayin Lin1
1School of Pharmaceutical Science (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, P. R. China.
Objectives:
Infections caused by multidrug-resistant (MDR) bacteria, especially MDR Gram-negative bacteria, have posed a great challenge to healthcare systems globally. To address the shortage of effective antibiotics against MDR Gram-negative bacterial infections, two non-antibiotic drugs - auranofin (rheumatoid arthritis drug) and pentamidine (antiprotozoal drug) - are being repurposed to treat MDR Gram-negative bacteria by a combination approach.
Methods:
Chequerboard microdilution assay was used to determine the interaction of auranofin and pentamidine against drug-susceptible and MDR Gram-negative bacteria (Escherichia coli, Acinetobacter baumannii and Klebsiella pneumoniae). Fluorescence microscopy, scanning electron microscopy and inductively coupled plasma mass spectrometry were used to explore the mechanism of synergistic antibacterial effect.
Results:
These two non-antibiotic drugs displayed a strong synergistic antibacterial effect, with the fraction inhibitory concentration index ranging 0.094-0.506. The MIC of auranofin reduced by as much as ≥ 1024-fold when combined with pentamidine at sub-MIC. Fluorescence and inductively coupled plasma mass spectrometry analyses revealed that bacterial membrane disruption caused by pentamidine treatment at sub-MIC led to an increased intracellular auranofin content with the combination treatment. The enhanced auranofin uptake in bacteria resulted in efficient bacterial killing. More importantly, the auranofin/pentamidine combination slowed down auranofin resistance development in clinically isolated MDR bacteria (Klebsiella pneumoniae) more than the combination of auranofin and colistin, which is a last-line antibiotic with a membrane-lytic antibacterial mechanism.
Conclusion:
The combination of non-antibiotic drugs with complementary antibacterial mechanisms provides a potentially promising approach to discover new antibacterial drugs and delay drug resistance development.
Insights
Repurposing non-antibiotic drugs auranofin and pentamidine shows strong synergistic effects against multidrug-resistant (MDR) Gram-negative bacteria. This combination enhances bacterial killing and slows resistance development, offering a promising strategy for combating MDR infections.
Area of Science:
- Microbiology
- Infectious Diseases
- Drug Discovery
Background:
- Multidrug-resistant (MDR) Gram-negative bacterial infections pose a significant global health challenge.
- There is an urgent need for novel therapeutic strategies to combat these infections due to the limited availability of effective antibiotics.
Purpose of the Study:
- To investigate the synergistic antibacterial effects of repurposing auranofin and pentamidine against MDR Gram-negative bacteria.
- To explore the mechanism underlying the synergistic action and assess the potential for delaying drug resistance.
Main Methods:
- Chequerboard microdilution assays were employed to evaluate drug interactions.
- Fluorescence microscopy, scanning electron microscopy, and ICP-MS were used to elucidate the mechanism of action.
Main Results:
- Auranofin and pentamidine exhibited strong synergistic activity against MDR Gram-negative bacteria, significantly reducing the minimum inhibitory concentration (MIC) of auranofin.
- Pentamidine at sub-inhibitory concentrations disrupted bacterial membranes, enhancing intracellular auranofin uptake and leading to efficient bacterial killing.
- The auranofin/pentamidine combination demonstrated a superior ability to slow resistance development compared to auranofin/colistin in MDR Klebsiella pneumoniae.
Conclusions:
- Combining non-antibiotic drugs with complementary mechanisms offers a promising avenue for developing new antibacterial agents.
- This approach holds potential for overcoming MDR bacterial infections and mitigating the emergence of drug resistance.
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