Virulence blockers as alternatives to antibiotics: type III secretion inhibitors against Gram‐negative bacteria

Abstract

In recent years mounting problems related to antibiotic-resistant bacteria have resulted in the prediction that we are entering the preantibiotic era. A way of preventing such a development would be to introduce novel antibacterial medicines with modes of action distinct from conventional antibiotics. Recent studies of bacterial virulence factors and toxins have resulted in increased understanding of the way in which pathogenic bacteria manipulate host cellular processes. This knowledge may now be used to develop novel antibacterial medicines that disarm pathogenic bacteria. The type III secretion system (T3SS) is known to be a potent virulence mechanism shared by a broad spectrum of pathogenic Gram-negative bacteria that interact with human, animal and plant hosts by injecting effector proteins into the cytosol of host cells. Diseases, such as bubonic plague, shigellosis, salmonellosis, typhoid fever, pulmonary infections, sexually transmitted chlamydia and diarrhoea largely depend on the bacterial proteins injected by the T3SS machinery. Recently a number of T3SS inhibitors have been identified using screening-based approaches. One class of inhibitors, the salicylidene acylhydrazides, has been subjected to chemical optimization and evaluation in several in vitro and ex vivo assays in multiple bacterial species including Yersinia spp., Chlamydia spp., Salmonella spp. and Pseudotuberculosis aeruginosa. Reports published up to date indicate that T3SS inhibitors have the potential to be developed into novel antibacterial therapeutics.

Type I Signal Peptidase and Protein Secretion inStaphylococcus epidermidis

“…From the perspective of potential drug development, it is interesting that much recent interest has focused on the targeting of virulence mechanisms (5,18,29). Nonetheless, approaches based on inhibiting virulence will likely suffer from a limited spectrum, as most proteins that contribute to virulence are not essential and thus free to diverge.…”

Antimicrobial Susceptibility Profiles of Environmental Enterobacteriaceae Isolates From Karun River, Iran

“…The same resistance has also been found in bacteria isolated from rural groundwater supplies and wild mammals (9). For example, classification of known tetracycline resistance genes is presented (3,10) in Table 5.…”

“…This resistance is a major public health problem worldwide, and affects the veterinary field too (2). Antibiotic-resistant bacteria are responsible for increased mortality (3). Bacterial resistance to antibiotics may be arises for several reasons particularly by mutations (4).…”

Solving the Supply of Resveratrol Tetramers from Papua New Guinean Rainforest Anisoptera Species That Inhibit Bacterial Type III Secretion Systems

“…26 Another advantage of virulence inhibitors is that cross-resistance is unlikely to evolve within or be transmutable to the beneficial microflora which do not possess T3SS machinery. 27 Lastly, since virulence blockers have a low impact on bacterial growth, selective pressure in favour of drug resistance is reduced and such mutations might result in dysfunctional virulence systems, and consequently the development of less virulent bacteria. 4,27,28 To date, multiple approaches towards identifying T3SS inhibitors have been undertaken.…”