At the 33rd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2023) held in Copenhagen, Dr. Xiaoting Hua of the Sir Run Run Shaw Hospital affiliated with Zhejiang University School of Medicine unveiled significant findings. His research focused on mutations that mediate Acinetobacter baumannii’s resistance and virulence to a new antibiotic, Cefiderocol.
Background:
Acinetobacter baumannii, one of the clinically paramount pathogens, has shown an increasing trend in both its clinical isolation rate and antibiotic resistance. Data from China Antimicrobial Surveillance Network (CHINET) indicates that in 2021, the resistance rate of Acinetobacter species to most antibiotics ranged from 48.4% to 69.8%, excluding polymyxins and tigecycline.
The emergence of Cefiderocol, a novel siderophore cephalosporin, has been promising due to its potent antibacterial activity against Gram-negative bacteria. However, resistance mechanisms involving β-lactamases and mutations in the iron transport system have started to appear. Recent studies, including those from Dr. Yunsong Yu and Dr. Xiaoting Hua, emphasize the role of the β-lactamase PER-1 in this resistance.
Methods and Results:
Delving deeper into this mechanism, Dr. Hua’s team performed whole-genome sequencing on Cefiderocol-resistant strains. Two pivotal mutations were identified – BaeS (D89V) and BaeR (S104N). These mutations were found to cause an 8-16 fold increase in the antibiotic’s minimum inhibitory concentration (MIC) when introduced into the reference strain ATCC 17978.
Further experiments, including transcriptomic analysis, gene knockout, and overexpression tests on the BaeS and BaeR mutations, were carried out. The results revealed that the mutations lead to an upregulation of efflux pumps like MacAB-TolC or MFS transporter proteins. This discovery was corroborated with findings that the BaeS (D89V) mutation also increased virulence in a Galleria mellonella infection model.
Conclusion:
The two-component system mutations BaeS (D89V) and BaeR (S104N) play a pivotal role in mediating the resistance of Acinetobacter baumannii to Cefiderocol. These mutations lead to an upregulation of specific genes and affect the bacterium’s overall virulence. As the medical community races against time to counteract antibiotic resistance, such insights are invaluable. They pave the way for a deeper understanding of resistance mechanisms and potentially offer avenues for new therapeutic strategies.
*Sources referenced from ECCMID 2023, CHINET, and the journal “Antimicrob Agents Chemother.”*
Dr. Xiaoting Hua
Zhejiang University School of Medicine, Sir Run Run Shaw Hospital
