Pharmacological Targeting of the Host-Pathogen Interaction: Alternatives to Classical Antibiotics to Combat Drug-Resistant Superbugs

Abstract

The rise of multidrug-resistant pathogens and the dearth of new antibiotic development place an existential strain on successful infectious disease therapy. Breakthrough strategies that go beyond classical antibiotic mechanisms are needed to combat this looming public health catastrophe. Reconceptualizing antibiotic therapy in the richer context of the host-pathogen interaction is required for innovative solutions. By defining specific virulence factors, the essence of a pathogen, and pharmacologically neutralizing their activities, one can block disease progression and sensitize microbes to immune clearance. Likewise, host-directed strategies to boost phagocyte bactericidal activity, enhance leukocyte recruitment, or reverse pathogen-induced immunosuppression seek to replicate the success of cancer immunotherapy in the field of infectious diseases. The answer to the threat of multidrug-resistant pathogens lies 'outside the box' of current antibiotic paradigms.

Keywords: antibiotic resistance; bacterial infections; immunotherapy; macrophages; neutrophils; virulence factors.

Figure 1. Potential for novel infectious disease therapeutics targeting the host-pathogen interface

Classical antibiotics, drugs that kill or suppress the growth of pathogens, have been the cornerstones of infectious disease therapy for decades. However, continual evolution of antibiotic resistance has eroded their once reliable efficacy. Considering serious bacterial infection as a perturbation of the host-pathogen interaction, novel therapeutic drug classes are under evaluation. These drugs seek to inhibit bacterial toxins and immune resistance factors, or stimulate immune cell resilience and expression of antimicrobial effectors.

Figure 2. Potential targets for pathogen-directed anti-virulence therapies against multidrug-resistant bacterial pathogens

Small molecules, nanoparticles, engineered proteins or monoclonal antibodies are under investigation to block expression or function of bacterial toxins and other virulence factors. Anti-virulence therapies hold promise of being more specific to the infectious bacterium while sparing the healthy microbiome, and can be used as adjuncts to classical antibiotics for difficult infections.

Figure 3. Potential targets for host-directed immune boosting therapies against multidrug-resistant bacterial pathogens

Taking advantage of evolving knowledge regarding chemokines and cytokines, pattern recognition receptors, and the regulatory programs they control, pharmacological approaches are being explored to boost the intrinsic antibacterial activity of macrophages and neutrophils.