Acinetobacter baumannii, a leading cause of hospital-acquired infections, is notorious for its multidrug resistance and persistence in clinical settings. A recent study led by Yuqin Song and Jie Feng from the Institute of Microbiology, Chinese Academy of Sciences, has uncovered a previously unrecognized mechanism that helps this pathogen adapt to the host: insertion sequence (IS)-mediated gene amplification. The findings, published in mLife, challenge the conventional view that IS-mediated amplification primarily drives antimicrobial resistance and highlight a delicate balance between host adaptation and antibiotic resistance.
The researchers analyzed 582 complete A. baumannii genomes and found that the insertion sequence ISAba1 was most frequently associated with gene amplification. Beyond known resistance genes, they identified a recurrently amplified crp-osmC gene cluster flanked by ISAba1 elements, which they designated the composite transposon Tn7691. Examining 7,490 genomes, they discovered a strong association between Tn7691 and crp-osmC amplification with the globally prevalent high-risk ST2 lineage, suggesting that this genetic structure may contribute to the success of this epidemic clone.
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 showed improved growth at later stages and a clear competitive advantage in vitro. More importantly, it exhibited enhanced fitness in mouse models of pulmonary infection and intestinal colonization, as well as improved survival in mouse serum. These results indicate that crp-osmC amplification promotes host-associated adaptation, a trait that could facilitate colonization and infection in patients.
Transcriptomic analysis revealed that crp-osmC amplification was linked to increased expression of genes involved in phenylalanine metabolism, siderophore biosynthesis, and sulfur metabolism, potentially enhancing metabolic flexibility and nutrient acquisition under nutrient-limited host conditions. The researchers further demonstrated that the cAMP receptor protein (CRP) retained its DNA-binding activity and directly bound the promoter of the siderophore-associated bas gene cluster, supporting its role in iron acquisition. This mechanistic insight helps explain how the amplification confers a fitness advantage in the host environment.
However, the adaptive benefit came with apparent costs. The amplified strain showed 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 an evolutionary trade-off: the same genetic change that enhances host fitness may compromise the ability to form biofilms and resist antibiotics. This trade-off could have significant clinical implications, as it may influence the persistence and treatment of A. baumannii infections. Understanding these dynamics could inform strategies to combat this pathogen, for instance by exploiting its increased antibiotic susceptibility when it adapts to the host.
By expanding the known functions of IS-mediated gene amplification beyond antimicrobial resistance, this study provides new insights into the genomic plasticity and adaptive evolution of A. baumannii. It underscores the importance of considering host-associated fitness in the development of therapeutics and highlights how bacterial pathogens can rapidly evolve to thrive in different environments, often with unintended consequences for their resistance profiles.
