Beyond Antibiotics: New Therapeutic Approaches for Bacterial Infections

Abstract

The utility of conventional antibiotics for the treatment of bacterial infections has become increasingly strained due to increased rates of resistance coupled with reduced rates of development of new agents. As a result, multidrug-resistant, extensively drug-resistant, and pandrug-resistant bacterial strains are now frequently encountered. This has led to fears of a "postantibiotic era" in which many bacterial infections will be untreatable. Alternative nonantibiotic treatment strategies need to be explored to ensure that a robust pipeline of effective therapies is available to clinicians. In this review, we highlight some of the recent developments in this area, such as the targeting of bacterial virulence factors, utilization of bacteriophages to kill bacteria, and manipulation of the microbiome to combat infections.

Keywords: antivirulence therapy; bacteria; microbiome; phage therapy; secretion systems.

Figure 1.

Strategies to block the cellular effects of anthrax toxin. Red arrows indicate critical steps in the intoxication process blocked by inhibitory compounds. Anthrax toxin is comprised of 3 proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). In the first step of the cell entry process, PA binds to receptors such as CMG2 on the surface of host cells. This interaction may be prevented by CMG2-Fc, a fusion protein consisting of the extracellular domain of CMG2 and human IgG Fc. Exogenously administered CMG2-Fc acts as a decoy receptor that sequesters PA before it binds to host cells (A). The interaction of PA with host cells can also be prevented by antibodies such as raxibacumab (GlaxoSmithKline) and obiltoxaximab (Elusys Therapeutics) that recognize and block host cell receptors (B). After binding its receptor, PA is cleaved by the host cell protease furin, a process that is blocked by the protease inhibitor IαIp (C). This cleavage event allows PA to oligomerize and form a prepore complex capable of binding the other 2 components of anthrax toxin, LF and EF. The monoclonal antibodies AVP-21D9 (Avanir Pharmaceuticals) and MDX1303 (PharmAthene/Medarex) block or disrupt the formation of the oligomer (D), and a heptavalent inhibitory peptide compound [17] blocks binding of LF to the oligomerized PA (E). The prepore complex bound to LF/EF then triggers endocytosis, and subsequent acidification of the endosome causes a structural change in the prepore complex that makes it competent to translocate LF/EF into the cytosol. The monoclonal antibody cAB29 and dominant-negative variants of PA (eg, V377E or F427A) prevent the formation of a functioning pore, blocking translocation of LF/EF into the cytosol (F). Likewise, the cationic compound AMBnTβCD effectively obstructs the pore (F). Once in the cytosol, LF and EF use their enzymatic activities to disrupt cellular processes. The monoclonal antibodies p6CO1/p6FO1 and the small-molecule inhibitor PT-8541 neutralize the activity of LF, whereas the monoclonal antibody EF13D and the small-molecule inhibitor DC-5 neutralize the activity of EF (G). A complete list of compounds targeting anthrax toxin as well as references for the preceding discussion can be found in [18, 19].

Figure 2.

Overview of antivirulence agents active against the type 3 secretion (T3S) system of Pseudomonas aeruginosa. Red arrows indicate the molecular targets of agents in development to prevent intoxication by the T3S system. ExsA is a transcriptional activator that induces expression of all genes in the T3S regulon. This induction is blocked by N-hydroxybenzimidazoles [22] (A). T3S genes encode proteins such as the PscF monomer, which polymerizes to form the needle complex. PscF is thought to be targeted by phenoxyacetamide compounds [23, 24] (B). PcrV is located at the tip of the needle complex and is essential for insertion of the translocation pore into the plasma membrane of the host cell. This protein is targeted by antibodies KB001 (KaloBios) [21] and MEDI3902 (AstraZeneca) [25] (C). Effector proteins ExoU and ExoS are injected into the host cell, where they manifest enzymatic activities that damage or subvert these cells. The activity of ExoU is inhibited by pseudolipasin A [26] and that of ExoS is inhibited by exosin and STO1101 [27, 28] (D).