Chemical Inhibitors of the Type Three Secretion System: Disarming Bacterial Pathogens

Abstract

The recent and dramatic rise of antibiotic resistance among bacterial pathogens underlies the fear that standard treatments for infectious disease will soon be largely ineffective. Resistance has evolved against nearly every clinically used antibiotic, and in the near future, we may be hard-pressed to treat bacterial infections previously conquered by "magic bullet" drugs. While traditional antibiotics kill or slow bacterial growth, an important emerging strategy to combat pathogens seeks to block the ability of bacteria to harm the host by inhibiting bacterial virulence factors. One such virulence factor, the type three secretion system (T3SS), is found in over two dozen Gram-negative pathogens and functions by injecting effector proteins directly into the cytosol of host cells. Without T3SSs, many pathogenic bacteria are unable to cause disease, making the T3SS an attractive target for novel antimicrobial drugs. Interdisciplinary efforts between chemists and microbiologists have yielded several T3SS inhibitors, including the relatively well-studied salicylidene acylhydrazides. This review highlights the discovery and characterization of T3SS inhibitors in the primary literature over the past 10 years and discusses the future of these drugs as both research tools and a new class of therapeutic agents.

Antibiotic resistance—the need for global solutions

“…Several small molecule inhibitors of type 3 secretion systems have been identifi ed including salicylidene acylhydrazides that are eff ective against several pathogens including Chlamydia spp, E coli, S enterica, and Shigella fl exneri. 366 Many pathogens, such as C diffi cile, V cholerae, Bordetella pertussis, E coli, and Bacillus anthracis, secrete extracellular toxins that contribute greatly to virulence. These toxins are often enzymes and have been targeted by screening campaigns to identify inhibitors that attenuate virulence.…”

The structure of the Slrp–Trx1 complex sheds light on the autoinhibition mechanism of the type III secretion system effectors of the NEL family

“…In Gram-negative pathogens, the translocated proteins, named effectors, are directly delivered into the hostcell cytoplasm through the type-III secretion system (T3SS), which displays a needle-like structure [1]. The T3SS offers an interest as target for the design of new antibiotics [2]. However, another therapeutic approach consists in targeting the secreted effectors that, once delivered by the T3SS, play critical roles in manipulating the host cell to allow for bacterial invasion, intracellular survival and proliferation [3,4].…”

Synthetic Cyclic Peptomers as Type III Secretion System Inhibitors

“…Because of the abundance of commensals within a mammalian host (10 13 to 10 14 ), antibiotic resistance is thought to arise more frequently in commensal bacteria and is horizontally transferred to pathogens (2)(3)(4). In contrast to classic antibiotics, virulence blockers are compounds that selectively inhibit the expression or function of a virulence factor in a pathogen or group of pathogens (5). Advantages of virulence blockers are twofold.…”