Mitigating the Impact of Antibacterial Drug Resistance through Host-Directed Therapies: Current Progress, Outlook, and Challenges

Abstract

Increasing incidences of multidrug resistance in pathogenic bacteria threaten our ability to treat and manage bacterial infection. The development and FDA approval of novel antibiotics have slowed over the past decade; therefore, the adoption and improvement of alternative therapeutic strategies are critical for addressing the threat posed by multidrug-resistant bacteria. Host-directed therapies utilize small-molecule drugs and proteins to alter the host response to pathogen infection. Here, we highlight strategies for modulating the host inflammatory response to enhance bacterial clearance, small-molecule potentiation of innate immunity, and targeting of host factors that are exploited by pathogen virulence factors. Application of state-of-the-art "omic" technologies, including proteomics, transcriptomics, and image-omics (image-based high-throughput phenotypic screening), combined with powerful bioinformatics tools will enable the modeling of key signaling pathways in the host-pathogen interplay and aid in the identification of host proteins for therapeutic targeting and the discovery of host-directed small molecules that will regulate bacterial infection. We conclude with an outlook on research needed to overcome the challenges associated with transitioning host-directed therapies into a clinical setting.

Keywords: antibiotic resistance; fluorescent image analysis; inflammation; innate immunity; multidrug resistance; proteomics.

FIG 1

Life cycle of intracellular bacteria. M. tuberculosis inhibits the fusion of late endosomes with mycobacterium-containing vacuoles. S. enterica survives and replicates within a Salmonella-containing vacuole by avoiding or delaying fusion with lysosomes. C. burnetii develops various strategies to resist hostile host defense within the lysosomes and allows phagosomal trafficking to proceed all the way to lysosomal fusion. F. tularensis escapes the vacuole and replicates within the cytosol. F. tularensis can reenter the endosomal compartment by entering an autophagosome. Bacteria that escape into the cytosol can gain intracellular motility by forming actin tails, which also helps bacteria to spread into adjacent cells through membrane protrusion. B. pseudomallei and B. mallei can induce MNGC formation and promote cell-to-cell spread.

FIG 2

Strategies to promote antibacterial responses by modulating host immune responses. (A) Regulating pattern recognition receptor signaling pathways. CASP1, caspase 1; IKK, IκB kinase. (B) Targeting negative regulators of the autophagy machinery. CTSB, cathepsin B. (C) Stabilizing hypoxia-inducible factor 1α. (D) Modulating the production of ROS and RNS.

FIG 3

Identifying host targets that mediate bacterial infection through multiomics approaches. Integrative multiomics approaches encompass the following. (Top left) Transcriptomic studies enable quantitative measurements of the dynamic changes in mRNA expression at the genome scale. (Top right) The cell-based HCI assay enables the extraction of hundreds of cellular and subcellular morphological features that are associated with bacterial infections at the single-cell level. (Bottom left) Metabolomic studies reveal metabolites that are generated in response to infection. (Bottom right) Proteomic studies facilitate the characterization and quantitation of proteome changes from samples.