Exploitation of Antibiotic Resistance as a Novel Drug Target: Development of a β-Lactamase-Activated Antibacterial Prodrug

Abstract

Expression of β-lactamase is the single most prevalent determinant of antibiotic resistance, rendering bacteria resistant to β-lactam antibiotics. In this article, we describe the development of an antibiotic prodrug that combines ciprofloxacin with a β-lactamase-cleavable motif. The prodrug is only bactericidal after activation by β-lactamase. Bactericidal activity comparable to ciprofloxacin is demonstrated against clinically relevant E. coli isolates expressing diverse β-lactamases; bactericidal activity was not observed in strains without β-lactamase. These findings demonstrate that it is possible to exploit antibiotic resistance to selectively target β-lactamase-producing bacteria using our prodrug approach, without adversely affecting bacteria that do not produce β-lactamase. This paves the way for selective targeting of drug-resistant pathogens without disrupting or selecting for resistance within the microbiota, reducing the rate of secondary infections and subsequent antibiotic use.

The Odd Couple(s): An Overview of Beta-Lactam Antibiotics Bearing More Than One Pharmacophoric Group

“…Probably the most recent example of a combination of a cephalosporin moiety and a quinolone is the cephalosporin-fluoroquinolone hybrid molecule developed by Evans and coworkers [ 68 ]. Their compound has been designed to be selectively activated in bacteria expressing β-lactamase.…”

Antibacterial Prodrugs to Overcome Bacterial Resistance

“…A cephalosporin analog with a methyl group at the α-position relative to the amide carbonyl of the reference compound cephalothin gave the best results. Overall, the prodrug exhibited a β-lactamase-mediated intracellular release of ciprofloxacin upon cleavage of the cephalosporin (Figure 4), selectivity toward β-lactamase-expressing E. coli, no activity on non-β-lactamase expressing bacteria, and very little activity of the intact prodrug [22]. This strategy of prodrug application opens the gate for using broad-spectrum antibiotics to treat resistant pathogens in a selective manner.…”

“…A novel cephalosporin-fluoroquinolone prodrug was developed by Evans et al [22]. The prodrug was designed to selectively deliver a broad-spectrum antibiotic, ciprofloxacin, to only β-lactamase expressing bacteria, while having minimal effects on bacteria that do not express this feature of resistance, the β-lactamase enzymes.…”

Recent Strategies in Design of Antitumor and Antibacterial Fluoroquinolones

“…Another example is the cephalosporin−ciprofloxacin prodrug, this prodrug was selectively activated by β-lactamase producing bacteria and only showed bactericidal activity after activation by a β-lactamase enzyme. This is a new strategy for selective targeting of drugresistant pathogens without disrupting the host bacteria, reducing the rate of secondary infections and drug side effect, besides, a broad spectrum of activity [133]. It is known that EMAU, 6-(3-ethyl-4-methylanilino) uracil derivatives are a new class of antibacterial agents that exhibited bactericidal activities toward a variety of Gram-positive bacterial species, because of their ability to inhibit polymerase IIIC enzyme and DNA synthesis.…”

“…For example, uropathogenic E. coli (UPEC) is a major cause of UTIs and frequently expresses β-lactamase. The prodrug is expected to result in high concentrations of active ciprofloxacin at the site of infection (bladder and kidneys), without disrupting the host microbiota [133].…”