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 host environment, potentially explaining its success as a nosocomial pathogen. The study, led by Yuqin Song and Jie Feng from the Institute of Microbiology, Chinese Academy of Sciences, and published in mLife, identifies insertion sequence-mediated gene amplification as a key driver of host-associated fitness in A. baumannii.
The researchers 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. 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, suggesting that this genetic structure may contribute to the lineage's epidemiological success.
To determine the biological significance of this amplification, the team experimentally increased the copy number of the crp-osmC cluster in A. baumannii. The amplified strain exhibited 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. These findings support a role for crp-osmC amplification in host-associated adaptation, particularly in nutrient-limited conditions.
Transcriptomic analysis revealed that crp-osmC amplification was linked to increased expression of genes involved in phenylalanine metabolism, siderophore biosynthesis, and sulfur metabolism, which may enhance metabolic flexibility and nutrient acquisition. The researchers further demonstrated that CRP retains its DNA-binding activity and directly binds the promoter of the siderophore-associated bas gene cluster, supporting its regulatory role in iron acquisition.
However, the adaptive advantage appears to come with costs. The amplified strain showed reduced expression of genes involved in pili and biofilm formation, resulting in decreased biofilm formation. Unexpectedly, crp-osmC amplification also increased susceptibility to multiple antibiotics. These findings suggest a trade-off between host-associated fitness and antibiotic resistance in A. baumannii.
This study expands the conventional view that insertion sequence-mediated gene amplification primarily drives antimicrobial resistance. It demonstrates that ISAba1-mediated amplification can also reshape host-associated fitness, providing new insights into the genomic plasticity, adaptive evolution, and clinical success of A. baumannii. Understanding these mechanisms could inform strategies to combat this resilient pathogen.
