Genetic and molecular mechanisms of multidrug-resistance in uropathogens and novel therapeutic combat

Abstract

Urinary tract infections (UTIs) affect the kidney, ureters, bladder, and urethra. UTIs are divided into pyelonephritis (inflammation of kidney), urethritis (urethral inflammation) and cystitis (inflammation or infection in bladder). UTIs are caused by gram-negative bacteria like E.coli, Proteus spp., Klebsiella spp., Pseudomonas aeruginosa and Acinetobacter spp. Gram-negative bacteria more commonly cause UTIs as compared to gram-positive bacteria. Some gram-positive bacteria including Staphylococcus aureus, coagulase-negative Staphylococci and Enterococcus spp. can also cause UTIs. UTIs are treated by using different groups of broad-spectrum antibiotics. Gradually, genetic mutations in essential proteins involved in the antibacterial activity such as mutations in antibiotics bind proteins (Penicillin-binding proteins, PBPs), mutations in proteins involved in antibiotic uptake (such as Porin channels), efflux system (active transport of antibiotics) or degradation (such as β-lactamases including extended-spectrum β-lactamases, penicillinases, carbapenemases and cephalosporinases). β-lactamases are produced by Enterobacteriaceae due to genetic mutations (such as CTX-M, OXA, KPC genes), which lead to the production of β-lactamases and subsequent degradation of antibiotics containing β-lactam ring. Recently, multidrug resistance uropathogens have been increased remarkably due to excessive use of antibiotics, self-medication, prolonged stay in the hospital, antibitics use without clinical diagnosis and genetic variation in these bacteria. This chapter will be focused on the pathogenesis of multi-drug resistant uropathogens (such as MDR, MRSA, ESBLs, VRE) in UTIs and their virulence factor and genetic variation, which will be helpful for the development of novel anti-virulence therapies and vaccine. The molecular mechanisms involved in drug resistance and novel therapeutic targeting of uropathogens will be discussed in detail.