Deciphering the Minimal Metalloproteome Essential to Mycoplasma Survival – MIMESIS

Transition metals are required by all life forms to carry out central functions necessary for survival. Moreover, they are at the heart of the host-pathogen battle as the host immune system sequesters essential metals from pathogens. In order to acquire metals and maintain their metal homeostasis, microbial pathogens have developed vital mechanisms involving a range of proteins that constitute their metalloproteome. Bacteria of the Mycoplasma genus have amongst the smallest genomes known for an autonomously replicating cell. Through evolution, genomes of mycoplasmas underwent drastic reduction to select a minimal set of essential genes. As such, the metalloproteome of mycoplasmas might represent a minimal metalloproteome required to perform some of the most fundamental functions supporting life. Many mycoplasmas are pathogens of vertebrates that are alarming in the raise of antimicrobial resistance, e.g., the avian pathogen Mycoplasma gallisepticum and the human pathogen Mycoplasma pneumoniae causing respiratory diseases. An attractive way to design drugs against these pathogens is to target essential components of their metalloproteome. However, microbial metalloproteomes are largely uncharacterized, especially in mycoplasmas. The MIMESIS project aims to decipher the mechanisms of metal acquisition and utilization in the minimalist mycoplasma organisms through a multidisciplinary approach combining biochemistry, structural biology, biophysics and bioinformatics. The project will unravel new biochemical mechanisms and answer fundamental questions regarding the metal homeostasis and metalloenzyme chemistry essential to minimal microbial pathogens. Ultimately, the project will identify key components in the survival of mycoplasmas, thereby uncovering putative new drug targets in order to combat antimicrobial resistance.