Multidrug-resistant pathogens (MDR) are a major threat to public health leading to chronic illness and prolonged hospital visits. The Center for Disease Control (CDC) estimates an additional $20 billion healthcare costs in the United States as a result MDR related illness. These infections can be life-threatening to immunocompromised patients and can be difficult to irradicate in a hospital setting. Despite the need for antibiotic development, the length of time required to fully bring a therapeutic to market coupled with the metabolic adaptability of MDR pathogens deters pharmaceutical companies from pursuing antibiotic related drug programs. The overall goal of this study was to characterize new therapeutic strategies for combating MDR related infections. Aim 1 focuses on Pseudomonas aeruginosa (Pa), which is a gram-negative opportunistic pathogen. Since iron is a key nutrient for Pa virulence, it was predicted that metallodrug and heme mimic gallium salophen (GaSal) would disrupt heme sensing and utilization, resulting in a bacteriostatic approach to combat infection. Work in Aim 1 contributes to understanding the role of heme metabolites biliverdin beta (BVIXβ) and biliverdin delta (BVIXδ) produced during Pa infection, characterizes relevant in vitro parameters related to drug development for a library of GaSal analogs, and finally assesses in vivo biodistribution and translatability of in vitro testing. Aim 2 shifts focus from pathogen to the host. All-trans retinoic acid (atRA), the main active metabolite of Vitamin A, is important for immune cell function and differentiation. Our lab has previously characterized an RAR gamma agonist to attenuate inflammation. The experiments in Aim 2 sought to determine how Vitamin A metabolism is disrupted during bacterial, viral, and fungal infection in the lung. In addition, we sought to investigate if there is potential dual utility to combat infection and abate inflammation by treating with RAR gamma agonist CD437. Overall, these studies further the understanding of targeting MDR pathogens while -also investigating the role that the host plays in the efficacy of antibiotics during infection.