Joint Transcriptional Control of Virulence and Resistance to Antibiotic and Environmental Stress in Acinetobacter baumannii

Abstract

The increasing emergence of antibiotic-resistant bacterial pathogens represents a serious risk to human health and the entire health care system. Many currently circulating strains of Acinetobacter baumannii exhibit resistance to multiple antibiotics. A key limitation in combating A. baumannii is that our understanding of the molecular mechanisms underlying the pathogenesis of A. baumannii is lacking. To identify potential virulence determinants of a contemporary multidrug-resistant isolate of A. baumannii, we used transposon insertion sequencing (TnSeq) of strain AB5075. A collection of 250,000 A. baumannii transposon mutants was analyzed for growth within Galleria mellonella larvae, an insect-based infection model. The screen identified 300 genes that were specifically required for survival and/or growth of A. baumannii inside G. mellonella larvae. These genes encompass both known, established virulence factors and several novel genes. Among these were more than 30 transcription factors required for growth in G. mellonella. A subset of the transcription factors was also found to be required for resistance to antibiotics and environmental stress. This work thus establishes a novel connection between virulence and resistance to both antibiotics and environmental stress in A. baumannii.

Clinical and Pathophysiological Overview of Acinetobacter Infections: a Century of Challenges

“…For example, Peleg et al found that A. baumannii was more lethal in the Galleria model than non-baumannii Acinetobacter species, including A. baylyi and A. lwoffii, and that antibiotic therapy improved survival of the infected larvae (75). Gebhardt et al also found that A. baumannii, even a strain considered to be avirulent (ATCC 17978), was more virulent than A. baylyi, in Galleria (76). Wand et al reported that strain to strain differences in biofilm formation did not correlate with virulence (77).…”

“…For example, A. baumannii grew better at 37°C and was better able to resist macrophage uptake than these other species in one study (86). As mentioned, A. baumannii strains were also more lethal to the wax moth larva of Galleria than strains of A. baylyi and A. lwoffii (75,76). In another study, a strain of A. junii was nonlethal in neutropenic mice, whereas several A. baumannii strains were lethal (85).…”

“…Many have made transposon mutant libraries in an effort to better understand Acinetobacter baumannii virulence phenotypes. These libraries have utilized transposon insertion sequencing (TnSeq) in an attempt to identify potential virulence determinants (76,(89)(90)(91). When combined, the current mutant collections and whole-genome sequencing provide an invaluable resource for both virulence and antibiotic susceptibility screenings (57,74,89,92).…”

Acinetobacter baumannii: Factors Involved in its High Adaptability to Adverse Environmental Conditions

“…Pathogenicity involves several virulence factors in combination with with metabolic capabilities and resistance to environmental stresses. Adaptation to stress involves intricate and interconnected regulatory pathways that integrate environmental signals with growth and survival decisions that in turn impact pathogenic potential [8][9][10][11].…”

“…Recent reports of the genetic requirements for A. baumannii persistence identify virulence factors as zinc and iron acquisition systems, capsule and LPS biosynthesis genes, amino acid metabolism and acquisition genes, and the bfmRS TCS but more studies are needed to increase knowledge in these aspects [10].…”