A new study led by Yuqin Song and Jie Feng from the Institute of Microbiology, Chinese Academy of Sciences, has uncovered a previously unrecognized mechanism by which the hospital pathogen Acinetobacter baumannii adapts to its host. The research, published in mLife, shows that amplification of the crp-osmC gene cluster, mediated by the insertion sequence ISAba1, enhances bacterial fitness in host environments but simultaneously reduces biofilm formation and increases susceptibility to several antibiotics.
Acinetobacter baumannii is a major cause of hospital-acquired infections, known for its multidrug resistance and ability to persist in clinical settings. By analyzing 582 complete genomes, the researchers found that ISAba1 was the insertion sequence most frequently associated with gene amplification. Beyond known resistance genes, they identified a recurrently amplified crp-osmC cluster flanked by ISAba1 elements, forming a composite transposon designated Tn7691. Analysis of 7,490 genomes revealed a strong association between Tn7691 and the globally prevalent high-risk ST2 lineage.
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 competitive advantage in co-culture. More importantly, it enhanced bacterial fitness in mouse models of pulmonary infection and intestinal colonization, and improved survival in mouse serum, supporting a role in host-associated adaptation.
Transcriptomic analysis provided insight into the mechanisms. Amplification was linked to increased expression of genes involved in phenylalanine metabolism, siderophore biosynthesis, and sulfur metabolism, potentially improving metabolic flexibility and nutrient acquisition under nutrient-limited 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 its regulatory role in iron acquisition.
However, the adaptive advantage came with costs. The amplified strain exhibited reduced expression of genes involved in pili and biofilm formation, and decreased biofilm formation. Unexpectedly, it 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 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 and clinical success of A. baumannii. For clinicians, the trade-off implies that strains adapting to the host may become more susceptible to certain antibiotics, potentially influencing treatment strategies. For researchers, it highlights the need to consider host adaptation mechanisms in the fight against multidrug-resistant pathogens.
