The increasing frequency of bacteria showing antimicrobial resistance (AMR) raises the menace of entering into a postantibiotic era. Horizontal gene transfer (HGT) is one of the prime reasons for AMR acquisition. Acinetobacter baumannii is a nosocomial pathogen with outstanding abilities to survive in the hospital environment and to acquire resistance determinants. Its capacity to incorporate exogenous DNA is a major source of AMR genes; however, few studies have addressed this subject. The transformation machinery as well as the factors that induce natural competence in A. baumannii are unknown. In this study, we demonstrate that naturally competent strain A118 increases its natural transformation frequency upon the addition of Ca 2Ű or albumin. We show that comEA and pilQ are involved in this process since their expression levels are increased upon the addition of these compounds. An unspecific protein, like casein, does not reproduce this effect, showing that albumin's effect is specific. Our work describes the first specific inducers of natural competence in A. baumannii. Overall, our results suggest that the main protein in blood enhances HGT in A. baumannii, contributing to the increase of AMR in this threatening human pathogen.A cinetobacter baumannii has emerged as a severe nosocomial pathogen over the course of the last few decades, with high levels of morbidity and mortality associated with infections by this pathogen (1, 2). A. baumannii is considered to be a paradigm of multidrug resistance since it has developed resistance to almost all available antibiotics, leaving few or no treatment options left. The ability of A. baumannii to persist in the clinical setting even under desiccation and nutrient starvation, as well as its ability to accumulate several antibiotic resistance determinants, allowed its evolution as a successful pathogen in the hospital environment (3).The large number of available A. baumannii genomes (n Ï 1,289) shows that foreign DNA is acquired at high frequencies (4-7).The transformation process has been well described for some species, such as Streptococcus pneumoniae, Vibrio cholerae, Neisseria meningitidis, and Helicobacter pylori (8-12). However, how natural competence is regulated has not been thoroughly studied, particularly for Gram-negative bacteria. Some well-characterized competence inducers are DNA damage in H. pylori (13), starvation, as was suggested for Haemophilus influenzae, and chitin metabolism in Vibrio cholerae (14,15). In most known examples, natural competence is a transitory state that is regulated by different internal and external signals. Often, these regulation networks are not completely understood. For Acinetobacter spp., most of the studies focusing on this issue were performed by using Acinetobacter baylyi strain ADP1 (16-20), a bacterium not as threatening to human health as A. baumannii (18-23). Data regarding A. baumannii and competence inducers are scarce (24-27). Wilharm et al. showed previously that several A. baumannii clinical isolates were a...