Mechanisms of rapid phenotypic variation in Acinetobacter baumannii and implications for diverse prokaryotes

Acinetobacter baumannii is a World Health Organisation “priority pathogen” of greatest risk to human health. The bacterium undergoes frequent phenotypic change, believed critical to its success. The mechanistic basis, and clinical implications, are not known. We have discovered a process never described for prokaryotes; specific A. baumannii gene clusters are “marked”, by chromosome folding, for frequent disruption by transposable DNA. Genes impacted are those involved in pathogenicity, and we propose this is how A. baumannii generates phenotypic variation in its populations. We will use diverse approaches, from single molecule to evolutionary in scale, to understand the mechanistic basis of our discovery. Using microbiology tools, infection models, and in collaboration with clinicians, we will determine the consequences in hospital environments. We will identify general rules explaining how targeted transposition allows A. baumannii, and other bacterial pathogens, to rapidly adapt to biotic and abiotic stress, including antibiotics, phage and the human immune system. Hypothesis: interplay of chromosome folding and transposition creates Acinetobacter baumannii population diversity needed for success in clinical environments Aim 1: Understand how chromosome folding directs transposition Aim 2: Understand how directed transposition controls clinically important phenotypes Aim 3: Understand how directed transposition impacts evolution of microbial communities