Navigating fluoroquinolone resistance in Gram-negative bacteria: a comprehensive evaluation

Abstract

Since the introduction of quinolone and fluoroquinolone antibiotics to treat bacterial infections in the 1960s, there has been a pronounced increase in the number of bacterial species that have developed resistance to fluoroquinolone treatment. In 2017, the World Health Organization established a priority list of the most critical Gram-negative resistant pathogens. These included Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli. In the last three decades, investigations into the mechanisms of fluoroquinolone resistance have revealed that mutations in the target enzymes of fluoroquinolones, DNA gyrase or topoisomerase IV, are the most prevalent mechanism conferring high levels of resistance. Alterations to porins and efflux pumps that facilitate fluoroquinolone permeation and extrusion across the bacterial cell membrane also contribute to the development of resistance. However, there is a growing observation of novel mutants with newer generations of fluoroquinolones, highlighting the need for novel treatments. Currently, steady progress has been made in the development of novel antimicrobial agents that target DNA gyrase or topoisomerase IV through different avenues than current fluoroquinolones to prevent target-mediated resistance. Therefore, an updated review of the current understanding of fluoroquinolone resistance within the literature is imperative to aid in future investigations.

Figure 1.

Skeletal structure of the core fluoroquinolone includes a bicyclic ring with carbonyls present on the C3 and C4 positions. Substitutions on the core structure generate different generations of fluoroquinolones: first generation nalidixic acid (a), second generation ciprofloxacin (b) and norfloxacin (c), third generation levofloxacin (d), and fourth generation moxifloxacin (e). Figure created with ChemDraw.

Figure 2.

Two fluoroquinolone molecules intercalate between the unpaired bases of DNA cleaved by DNA gyrase/topoisomerase IV to stabilize the enzyme-DNA cleavage. This ternary complex (enzyme-DNA-fluoroquinolone) inhibits DNA gyrase/topoisomerase IV activity such that it can no longer induce strand relaxation or negative supercoils.

Figure 3.

(a) 3D crystal structure of Acinetobacter baumannii topoisomerase IV complexed with DNA (purple) and 2 fluoroquinolone molecules, moxifloxacin (grey space filling representation). The DNA gate region is zoomed in on the right-hand side, the black arrow shows the interaction between the tyrosine residue and DNA. (b) C3 and C4 carbonyls on the fluoroquinolone form a bridging interaction to a Mg²⁺ ion forming an octahedral complex with four additional water molecules, two water molecules interact with serine and aspartic acid residues in GyrA or in ParC. Figure created with ChemDraw.

Figure 4.

Mechanism of fluoroquinolone resistance in Gram-negative bacteria can be classified into three key groups. Mutations in the target enzymes, DNA gyrase or topoisomerase IV (a), alteration to efflux pumps (b) and porins (c) which control the transport of fluoroquinolones or PMQR (d).

Figure 5.

(a) Quinazolinediones core shows lacks the keto acid moiety on quinazolinediones that usually forms the water-metal ion bridge in fluroquinolones. (b) Skeletal structure of the novel class of tricyclic imidazopyrazinones which lack the carboxylic acid moiety at the C3 present in fluoroquinolones. (c) Skeletal structure of the lead spiropyrimidinetrione of this class, AZD0914 (zoliflodacin) contains a benzisoxazole scaffold and a spirocyclic pyrimidinetrione core. (d) NBTIs contain a head group (left-hand side) which binds DNA and a tail region (right-hand side) that interacts with the target enzymes. These two regions are enjoined by a linker section. (e) Compound 814 is an alkylaminoquinolone derivative developed as an EPI to prevent the efflux of fluoroquinolones. Figure created with ChemDraw.