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Antibiotic resistance poses a major threat to global public health.
Quinolones are synthetic antibacterial drugs, including common levofloxacin, ciprofloxacin, moxifloxacin and so on.
Quinolones are used to treat a variety of bacterial infections, including tuberculosis.
Quinolone drugs inhibit the enzymatic activity of bacterial DNA gyrase and topoisomerase IV to block the DNA replication and RNA synthesis processes necessary for growth.
In clinical applications, the drug resistance of quinolone antibiotics is becoming more and more serious.
Studies have found that the pentapeptide repeat protein MfpA in mycobacteria regulates the activity of gyrase by mimicking DNA and participates in protecting it from fluoroquinolone drugs.
However, the mechanism of MfpA is still unclear.
This study revealed for the first time the new mechanism of MfpA involved in mycobacterial anti-fluoroquinolone drugs.
The research team purified MfpA from Mycobacterium smegmatis (a model strain of Mycobacterium tuberculosis) and tested its regulation of DNA gyrase activity.
The results showed that MfpA inhibited the supercoiling reaction of DNA gyrase.
Further studies have shown that MfpA can inhibit DNA damage caused by fluoroquinolone in the presence of ATP, thereby protecting bacteria from antibiotics (Figure 1).
Figure 1 MfpA's regulation of DNA gyrase activity Through X-ray crystallography, the complex of MfpA and DNA gyrase ATPase domain was analyzed (Figure 2).
Figure 2 MfpA and DNA gyrase ATPase domain complex structure combined with enzymatic detection results, we propose the mechanism of MfpA (Figure 3): MfpA directly interacts with the ATPase domain of DNA gyrase to activate the ATPase Activity, changes the conformation of DNA gyrase, and promotes the release of fluoroquinolones from the DNA gyrase-drug-DNA complex, and finally DNA gyrase completes the catalytic change of DNA topological structure under the protection of MfpA (Figure 3).
The analysis of the crystal structure of MfpA and DNA gyrase ATPase domain complex provides scientific ideas for the design of new antibiotics that inhibit DNA gyrase.
Figure 3 MfpA's mechanism of action diagram.
The related results are presented in the international journal Proceedings of the National Academy of Sciences of the United States of "The pentapeptide-repeat protein, MfpA, interacts with mycobacterial DNA gyrase as a DNA T-segment mimic" America announced.
Mi Kaixia from the Institute of Microbiology of the Chinese Academy of Sciences and Anthony Maxwell from the John Innes Centre are the co-corresponding authors of the paper, and the postdoctoral fellow Feng Lipeng is the first author of the paper.
Funding for this project comes from the Key R&D Program of the Ministry of Science and Technology, the National Natural Science Foundation of China, CEPAMS, BBSRC, etc.
Original link: https://https:// (Note: The cover is a schematic diagram)
Quinolones are synthetic antibacterial drugs, including common levofloxacin, ciprofloxacin, moxifloxacin and so on.
Quinolones are used to treat a variety of bacterial infections, including tuberculosis.
Quinolone drugs inhibit the enzymatic activity of bacterial DNA gyrase and topoisomerase IV to block the DNA replication and RNA synthesis processes necessary for growth.
In clinical applications, the drug resistance of quinolone antibiotics is becoming more and more serious.
Studies have found that the pentapeptide repeat protein MfpA in mycobacteria regulates the activity of gyrase by mimicking DNA and participates in protecting it from fluoroquinolone drugs.
However, the mechanism of MfpA is still unclear.
This study revealed for the first time the new mechanism of MfpA involved in mycobacterial anti-fluoroquinolone drugs.
The research team purified MfpA from Mycobacterium smegmatis (a model strain of Mycobacterium tuberculosis) and tested its regulation of DNA gyrase activity.
The results showed that MfpA inhibited the supercoiling reaction of DNA gyrase.
Further studies have shown that MfpA can inhibit DNA damage caused by fluoroquinolone in the presence of ATP, thereby protecting bacteria from antibiotics (Figure 1).
Figure 1 MfpA's regulation of DNA gyrase activity Through X-ray crystallography, the complex of MfpA and DNA gyrase ATPase domain was analyzed (Figure 2).
Figure 2 MfpA and DNA gyrase ATPase domain complex structure combined with enzymatic detection results, we propose the mechanism of MfpA (Figure 3): MfpA directly interacts with the ATPase domain of DNA gyrase to activate the ATPase Activity, changes the conformation of DNA gyrase, and promotes the release of fluoroquinolones from the DNA gyrase-drug-DNA complex, and finally DNA gyrase completes the catalytic change of DNA topological structure under the protection of MfpA (Figure 3).
The analysis of the crystal structure of MfpA and DNA gyrase ATPase domain complex provides scientific ideas for the design of new antibiotics that inhibit DNA gyrase.
Figure 3 MfpA's mechanism of action diagram.
The related results are presented in the international journal Proceedings of the National Academy of Sciences of the United States of "The pentapeptide-repeat protein, MfpA, interacts with mycobacterial DNA gyrase as a DNA T-segment mimic" America announced.
Mi Kaixia from the Institute of Microbiology of the Chinese Academy of Sciences and Anthony Maxwell from the John Innes Centre are the co-corresponding authors of the paper, and the postdoctoral fellow Feng Lipeng is the first author of the paper.
Funding for this project comes from the Key R&D Program of the Ministry of Science and Technology, the National Natural Science Foundation of China, CEPAMS, BBSRC, etc.
Original link: https://https:// (Note: The cover is a schematic diagram)
