Antibodies Inhibiting the Type III Secretion System of Gram-Negative Pathogenic Bacteria

Abstract

Pathogenic bacteria are a global health threat, with over 2 million infections caused by Gram-negative bacteria every year in the United States. This problem is exacerbated by the increase in resistance to common antibiotics that are routinely used to treat these infections, creating an urgent need for innovative ways to treat and prevent virulence caused by these pathogens. Many Gram-negative pathogenic bacteria use a type III secretion system (T3SS) to inject toxins and other effector proteins directly into host cells. The T3SS has become a popular anti-virulence target because it is required for pathogenesis and knockouts have attenuated virulence. It is also not required for survival, which should result in less selective pressure for resistance formation against T3SS inhibitors. In this review, we will highlight selected examples of direct antibody immunizations and the use of antibodies in immunotherapy treatments that target the bacterial T3SS. These examples include antibodies targeting the T3SS of Pseudomonas aeruginosa, Yersinia pestis, Escherichia coli, Salmonella enterica, Shigella spp., and Chlamydia trachomatis.

Molecular Targets and Strategies for Inhibition of the Bacterial Type III Secretion System (T3SS); Inhibitors Directly Binding to T3SS Components

“…When an inhibitor binds to the needle tip without blocking the pore it can still prevent binding of the tip to the translocon, creating a translocation blockade [ 102 ]. Many effector proteins cannot pass through the membrane after secretion, allowing them to stay within the host [ 26 ].…”

“…Multiple other small molecule and antibody inhibitors of adhesion targeting the intimate attachment of pathogenic E. coli have been discovered through the years [ 102 , 122 , 225 , 226 , 227 , 228 , 229 , 230 , 231 ]. Quercetin ( Figure 19 ) was recently implicated as an inhibitor by Xue et al while observing E. coli O157:H7, the EHEC strain most commonly causing outbreaks, adhesion to human colon adenocarcinoma-2 (Caco-2) cells.…”

“…( A ) Antibody inhibitors; Left : Antibody binding to the needle tip preventing binding to the translocon; Right : Antibody binding and physically preventing the secretion of effectors; ( B ) Small molecule inhibitors; Left : Translocation blockade caused by the inhibitor binding to the needle tip; Middle : Small molecule binding and physically preventing effector secretion; Right : Conformational change of needle tip protein caused by small-molecule binding. Image modified from [ 102 ]. Abbreviations: OM, outer membrane; PG, peptidoglycan; IM, inner membrane; HCM, host cell membrane.…”

Antibiotic Therapy of Plague: A Review

“…Antivirulence drug development has focused on type 3 secretion systems (T3SSs) and their associated toxins [ 154 ]. T3SSs are heteromultimer protein complexes produced by many Gram-negative bacteria, including Y. pestis [ 155 , 156 , 157 ]. In Y. pestis , the T3SS exports toxic Yersinia outer proteins (Yops) from the bacterium into the phagocyte.…”

Multiplicity of Glycosphingolipid-Enriched Microdomain-Driven Immune Signaling

“…Gram-negative pathogenic bacteria are known to use the type III secretion system (T3SS) to induce pore formation on host membranes [198,199]. Salmonella uses T3SS to rupture phagosomal membranes [176,177], releasing internalized bacteria into the cytoplasmic region of host cells and inducing autophagy (xenophagy) to eliminate these bacteria [200,201].…”