In vitro and in vivo characterization of FimH antagonists for anti-adhesion therapy - an alternative therapeutic approach against urinary tract infection

Uropathogenic Escherichia coli (UPEC) are the major cause of urinary tract infections (UTI), which is one of the most common infectious disease worldwide. Women belong to the most affected population, with every second woman experiencing at least one symptomatic UTI during her lifetime. Additionally, UTI is a major problem in the clinics, being the most common hospital acquired infection. To avoid complications like kidney infections, irreversible kidney damage or urosepsis, all symptomatic infections should be treated with antibiotics. The use of antibiotics for the treatment of UTI, is continuosly increasing the development of resistant pathogens against most of the currently available antimicrobials. Therefore, new treatment strategies targeting alternative mechanisms are urgently needed, avoiding selection pressure on bacteria and thereby implying a reduced risk of resistance.
An alternative approach for the treatment of UTI is the anti-adhesion therapy using FimH antagonists. FimH is an adhesin, located on the distal tip of type 1 pili, expressed on the surface of UPEC. The type 1 pilus contains a carbohydrate recognition domain, binding to mannose glycans expressed on urothelial cells. This allows UPEC to adhere to and to invade host cells within the urinary tract epithelium and is the initial step for a successful establishment of a UTI.
FimH antagonists are highly active anti-adhesion molecules, targeting the virulence factor FimH. In vitro and in vivo studies clearly indicate the potential of FimH antagonists for the prevention and treatment of UTI, with a higher therapeutic efficacy compared to antibiotics.
The anti-adhesion therapy is focusing on the development of a new class of antimicrobials exhibiting less selection pressure and therefore a reduced potential for the emergence of resistance. In addition, a reduction of the antibiotic associated side effects (e.g. the disruption of the commensal microbiota) is expected. Thus, the availability of a novel class of antimicrobials based on an alternative mode of action would have a huge impact on the treatment of UTI, being a substantial contribution to public health.