Acinetobacter baumannii, a leading cause of hospital-acquired infections, is notorious for its multidrug resistance and ability to persist in clinical settings. A new study led by Yuqin Song and Jie Feng from the Institute of Microbiology, Chinese Academy of Sciences, has uncovered a genetic mechanism that helps this pathogen adapt to the host environment, potentially explaining its clinical success. The research, published in mLife, identifies insertion sequence (IS)-mediated gene amplification as a driver of host-associated fitness, but also reveals a surprising trade-off that could influence treatment strategies.
The team analyzed 582 complete A. baumannii genomes and found that the insertion sequence ISAba1 was most frequently associated with gene amplification. Beyond known antimicrobial resistance genes, they discovered a recurrently amplified crp-osmC gene cluster flanked by ISAba1 elements, which they designated the composite transposon Tn7691. Further analysis of 7,490 genomes showed a strong association between Tn7691 and crp-osmC amplification with the globally prevalent high-risk ST2 lineage and its single-locus variants. This link suggests that the amplification event may have contributed to the spread and success of this clinically important lineage.
To test the biological significance, the researchers experimentally increased the copy number of the crp-osmC cluster in A. baumannii. The amplified strain displayed improved growth at later stages and a competitive advantage in vitro. More importantly, it showed enhanced fitness in mouse models of pulmonary infection and intestinal colonization, as well as improved survival in mouse serum. Transcriptomic analysis revealed that the amplification increased expression of genes involved in phenylalanine metabolism, siderophore biosynthesis, and sulfur metabolism, likely improving metabolic flexibility and nutrient acquisition under host conditions. The researchers further demonstrated that CRP retained DNA-binding activity and directly bound the promoter of the siderophore-associated bas gene cluster, supporting its role in iron acquisition.
However, the adaptive advantage came with apparent costs. The amplified strain exhibited reduced expression of genes involved in pili and biofilm formation, and decreased biofilm formation. Unexpectedly, crp-osmC amplification also increased susceptibility to multiple antibiotics. These findings suggest that enhanced host-associated fitness may be accompanied by a trade-off in antibiotic resistance. This challenges the conventional view that IS-mediated gene amplification primarily drives antimicrobial resistance and highlights the complex interplay between adaptation to the host and resistance to treatment.
The study expands our understanding of how genomic plasticity contributes to the clinical success of A. baumannii. By showing that ISAba1-mediated amplification can reshape host-associated fitness, it provides new insights into the adaptive evolution of this pathogen. The trade-off between host adaptation and antibiotic resistance may have implications for the development of treatment strategies, as strains with enhanced colonization ability might be more susceptible to certain antibiotics. Future research could explore whether this vulnerability can be exploited therapeutically. The work was supported by the National Key Research and Development Program of China and the National Natural Science Foundation of China.
