From screen to target: insights and approaches for the development of anti-virulence compounds

Abstract

A detailed understanding of host-pathogen interactions provides exciting opportunities to interfere with the infection process. Anti-virulence compounds aim to modulate or pacify pathogenesis by reducing expression of critical virulence determinants. In particular, prevention of attachment by inhibiting adhesion mechanisms has been the subject of intense research. Whilst it has proven relatively straightforward to develop robust screens for potential anti-virulence compounds, understanding their precise mode of action has proven much more challenging. In this review we illustrate this challenge from our own experiences working with the salicylidene acylhydrazide group of compounds. We aim to provide a useful perspective to guide researchers interested in this field and to avoid some of the obvious pitfalls.

Biofilm: A Robust and Efficient Barrier to Antifungal Chemotherapy

“…Improved antifungal strategies are therefore urgently required [13][14][15][16][17]. In this context, the anti-virulence strategy is in vogue and is a light at the end of the tunnel considering the limited antifungal armamentarium [18][19][20]. In theory, the anti-virulence therapy prevents the emergence of resistance against a particular drug, since it inhibits the expression of virulence attribute(s) that are essential for the development of infection, without inhibiting the microbial proliferation [18][19][20].…”

“…In this context, the anti-virulence strategy is in vogue and is a light at the end of the tunnel considering the limited antifungal armamentarium [18][19][20]. In theory, the anti-virulence therapy prevents the emergence of resistance against a particular drug, since it inhibits the expression of virulence attribute(s) that are essential for the development of infection, without inhibiting the microbial proliferation [18][19][20]. Fungi are able to produce an arsenal of virulence factors [21][22][23][24], including the ability to form biofilm in both biotic (e.g., host tissues such as the oral cavity, respiratory, gastrointestinal and urinary tracts) and abiotic surfaces (e.g., implanted medical devices such as venous catheters, cannulation, pacemakers, endotracheal tubes, ventriculoperitoneal shunts, prosthetic joints, breast implants, contact or intraocular lenses, stents, intrauterine contraceptive devices and dentures) [24][25][26][27].…”

Design, synthesis and evaluation of novel polypharmacological antichlamydial agents

“…1) are inhibitors of T3S in a number of gram-negative pathogens including Chlamydia spp. and Yersinia pseudotuberculosis [25]. T3S is a virulence system in many clinically relevant gram-negative bacteria that allows direct transfer of bacterial effector proteins, toxins, into the host cell and thereby promotes bacterial survival.…”

“…Yield: 29%; ESIMS m/z calcd for C 25 To the suspension of compound 14a (0.73 mmol) in MeOH (4 mL) at 0 C, was added 4 M HCl in 1,4-dioxane solution (8 mL) drop wise under nitrogen. The resulting mixture was stirred for overnight at ambient temperature under nitrogen.…”

Morin Moderates the Biotoxicity of Pneumococcal Pneumolysin by Weakening the Oligomers’ Formation

“…Antibiotics impose a strong selective pressure on bacteria, thereby increasing the probability of the emergence of resistance mechanisms. 19) Existing antibacterial agents act on the essential processes of growth in pathogens that hinder their multiplication or directly lyse the cells that can release cellular contents, particularly toxins that can damage host tissue. 20) Based on these observations, we investigated the cytotoxicity of morin against S. pneumoniae pneumolysinin vitro and its impact on S. pneumonia induction in a pneumonia mouse model.…”