Acinetobacter baumannii, a leading cause of hospital-acquired infections, is notorious for its multidrug resistance and ability to persist in clinical settings. New research has uncovered a genetic mechanism that helps this pathogen adapt to the human host, potentially explaining its success—and revealing a surprising vulnerability.
The study, led by Yuqin Song and Jie Feng from the Institute of Microbiology, Chinese Academy of Sciences, focused on insertion sequence (IS)-mediated gene amplification. By analyzing 582 complete A. baumannii genomes, the researchers found that the insertion sequence ISAba1 was most frequently associated with gene amplification. Beyond known antibiotic resistance genes, they identified a recurrently amplified crp-osmC gene cluster flanked by ISAba1 elements, forming a composite transposon designated Tn7691. Analysis of 7,490 genomes showed that Tn7691 and crp-osmC amplification are strongly associated with the globally prevalent high-risk ST2 lineage and its single-locus variants.
To test the biological significance, the team experimentally increased the copy number of the crp-osmC cluster. The amplified strain displayed improved growth at later stages and a competitive advantage in co-culture. 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 crp-osmC amplification boosted expression of genes involved in phenylalanine metabolism, siderophore biosynthesis, and sulfur metabolism, likely improving metabolic flexibility and nutrient acquisition under host conditions. The researchers also demonstrated that CRP retains DNA-binding activity and directly binds the promoter of the siderophore-associated bas gene cluster, supporting a 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 correspondingly 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.
The work, published in mLife, expands the conventional view that IS-mediated gene amplification primarily drives antimicrobial resistance. It demonstrates that ISAba1-mediated amplification can reshape host-associated fitness, providing new insights into the genomic plasticity, adaptive evolution, and clinical success of A. baumannii. Understanding these mechanisms could inform new strategies to combat infections by this resilient pathogen.
