Friday, April 26, 2024
4/26/2024
Nosocomial infections caused by gram-negative pathogens such as Acinetobacter baumannii have become a major challenge in the treatment of immunocompromised individuals and patients with traumatic injuries. These infections include ventilator-associated pneumonia, catheter-related urinary tract infections and non-healing wound infections that can ultimately lead to sepsis. Of significant concern is the increasing frequency of life- threatening infections caused by drug resistant A baumannii, reinforcing the need for new therapeutic approaches. Recent studies have shown that A. baumannii taxa are abundant in clinical environments and that decreases in microbial diversity contribute to increased antimicrobial resistance. However, little is known about the biological and physical interactions between Acinetobacter sp isolated from these environments. Characterization of a growing collection of Acinetobacter isolates obtained directly from patients at the University of Michigan Hospital System over a period of 5 years has identified “predator” strains of A. baumannii capable of inhibiting the growth of susceptible (“prey”) Acinetobacter strains. This phenotype is manifested as a zone of clearing of susceptible bacteria – embedded in soft agar - that emanates from centrally inoculated predator strains. Crude extracts containing a novel peptide toxin belonging to the family of ribosomally synthesized and posttranslationally modified peptides (RiPPs) can be isolated from the predator and subsequently added to prey strains resulting in cell contact-independent growth inhibition. Our preliminary data demonstrate that the presence of the genes predicted to be required for the synthesis, modification, and secretion of this RiPP, a novel peptide toxin, is relatively rare. Screening of our strain collection indicate that approximately 3 % carry the genes and display the growth inhibition phenotype. Analysis of available sequences in the NCBI database confirms the relatively scarceness of these genes. In contrast, several A. baumannii strains including multidrug resistant A. baumannii isolates as well as strains of the species Acinetobacter pittii are sensitive to killing. The primary objective of this study is to dissect these antagonistic interactions among Acinetobacter isolates. We aim to determine the nature of the peptide toxin and its mechanism of secretion. In addition, experiments are designed to reveal how the toxin enters susceptible strains and by what mechanism it inhibits their growth. These studies will advance our understanding of the role of the toxin and have significant translational implications with potential for precision drug therapy as the use of the toxin or variants thereof may represent a promising means of combating infections caused by multi-drug resistant A. baumannii.
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