UroPathogenic Escherichia coli (UPEC) Infections: Virulence Factors, Bladder Responses, Antibiotic, and Non-antibiotic Antimicrobial Strategies

Abstract

Urinary tract infections (UTIs) are one of the most common pathological conditions in both community and hospital settings. It has been estimated that about 150 million people worldwide develop UTI each year, with high social costs in terms of hospitalizations and medical expenses. Among the common uropathogens associated to UTIs development, UroPathogenic Escherichia coli (UPEC) is the primary cause. UPEC strains possess a plethora of both structural (as fimbriae, pili, curli, flagella) and secreted (toxins, iron-acquisition systems) virulence factors that contribute to their capacity to cause disease, although the ability to adhere to host epithelial cells in the urinary tract represents the most important determinant of pathogenicity. On the opposite side, the bladder epithelium shows a multifaceted array of host defenses including the urine flow and the secretion of antimicrobial substances, which represent useful tools to counteract bacterial infections. The fascinating and intricate dynamics between these players determine a complex interaction system that needs to be revealed. This review will focus on the most relevant components of UPEC arsenal of pathogenicity together with the major host responses to infection, the current approved treatment and the emergence of resistant UPEC strains, the vaccine strategies, the natural antimicrobial compounds along with innovative anti-adhesive and prophylactic approaches to prevent UTIs.

Keywords: antibiotics; bladder; non-antibiotic remedies; urinary tract infections; uropathogenic Escherichia coli.

Figure 1

The urinary tract and sites of infection.

Figure 2

Escherichia coli adhesins and harboring/motile structures.

Figure 3

The innate immune responses of bladder epithelium to bacterial infections. (A) The bladder epithelium; (B) adherent bacteria are internalized along with Rab27b+ fusiform vesicles; (C) exocytosis of RAB27b+ vesicles harboring UPEC and expulsion of the intracellular UPEC back into the lumen of the bladder; (D) transient receptor potential mucolipin 3 Ca2+ channel (TRPML3) triggers the spontaneous expulsion of the defective lysosomes and its contents out into the extracellular space; (E) soluble factors are also secreted by BECs, including antimicrobial peptides (AMP, such as cathelicidin and β-defensin 1), antimicrobial proteins [such as pentraxin 3 (PTX3)] and chemokines [such as CXC-chemokine ligand 1 (CXCL1) and CC-chemokine ligand 5 (CCR5)]. (F) Exfoliation is accompanied by rapid renewal of superficial BECs through active proliferation of basal progenitor mast cells. Intimate crosstalk between macrophages ensures the precise initiation of neutrophil responses.

Figure 4

Structure formulae of some UPEC resistant and susceptible antibiotics. UPEC resistance is shown with a red background, susceptibility with a green background, whereas the yellow background shows antibiotics that already show resistance in some UPEC strains.

Figure 5

Structure formulae of pilicide scaffold, some bioactive pilicides, and the curlicide FN075.

Figure 6

Structure formulae of d-mannose and some bioactive mannosides.

Figure 7

Structure formula of 25-hydroxyvitamin D₃.

Figure 8

Structure formulae of methenamine mandelate and hippurate.

Figure 9

Structure formulae of some polymeric phenolics.

Figure 10

Structure formulae of some non-polymeric phenolics.

Figure 11

Structure formulae of some representative bioactive compounds isolated from plant extracts exerting antimicrobial activity against UPEC listed in Table 1.

Figure 12

The four main areas representing the Strengths and the Weaknesses of UPEC, the Opportunities for alternative remedies to antibiotics and, finally, the Treats that UPEC cause to human health.