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New Approaches to Sensitize Multidrug-Resistant Gram-Negative Bacterial Pathogens to Host Innate Immune Clearance

  • Author(s): Munguia, Jason
  • Advisor(s): Nizet, Victor
  • et al.
Abstract

Multidrug-resistant Gram-negative (MDRGN) bacterial pathogens pose a significant threat to public health in the US and worldwide. The lack of therapeutic options for MDRGN bacterial infection have forced clinicians to use older, once rarely used antibiotics that are associated with significant toxicity. An increasing number of immunocompromised individuals, including the elderly, premature neonates, surgical patients, organ transplant recipients, and those receiving cancer chemotherapy, represent an expanding reservoir for MDRGN bacteria in the hospital setting. Research to understand the molecular host-pathogen interactions involved in MDRGN bacterial infections and reveal novel therapeutic targets are imperative if we are to prevent the advent of a post-antibiotic era.

For this PhD dissertation project, I began by searching for genes in the MDRGN bacterial pathogen Acinetobacter baumannii that are important in resisting the bactericidal action of the human cathelicidin antimicrobial peptide, LL-37, a critical front-line effector of host innate defense. A transposon insertion in vacJ, a component of the mla system conserved in all Gram-negative species, proved important in mediating resistance to LL-37, detergents, whole blood, complement, and neutrophils. A. baumannii lacking vacJ demonstrated reduced virulence compared to wild-type parent strain in a murine pneumonia model. To expand the general significance of this work, I examined the virulence capacity of multiple mla mutants in Pseudomonas aeruginosa, a leading MDRGN opportunistic human pathogen. P. aeruginosa lacking an mla system exhibited increased sensitivity to LL-37 and its murine homolog, as well as membrane active pharmaceuticals, serum, and whole blood. A murine pneumonia model revealed reduced bacterial burden and mortality when infected with bacteria lacking vacJ. Finally, I explored how a common antibiotic, azithromycin, traditionally considered ineffective against MDRGN bacteria in standard testing assays, gained entry to its ribosomal target when endogenous antimicrobial peptides modify the outer membrane, allowing it to provide clear efficacy in an in vivo model of A. baumannii pneumonia. Altogether, this dissertation furthered our understanding on the importance outer membrane integrity for Gram-negative bacteria to resist host immune clearance. This research points to a possible therapeutic target in the mla pathway to control MDRGN infections by sensitizing them to the host innate immune system.

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