Cranberry juice may help extend the life of a major urinary tract infection antibiotic by reprogramming the way bacteria absorb fosfomycin and develop resistance.
Study: Cranberry juice enhances the susceptibility of uropathogenic Escherichia coli (UPEC) strains to fosfomycin and reduces the development of spontaneous resistance. Image credit: New Africa/Shutterstock.com
In a recent study published in Applied and environmental microbiologyResearchers have shown that cranberry juice (CJ) enhances the antibacterial activity of fosfomycin (FOS) and reduces the development of resistance in uropathogenic diseases. Escherichia coli (UPEC).
Rising UTI resistance accelerates search for alternative treatments
UPEC is the main causative agent of urinary tract infections (UTIs) and can lead to a variety of complications, including kidney damage, sepsis, pyelonephritis, and chronic health problems. The increase in antimicrobial resistance (AMR) is a growing concern for UTI treatment. Therefore, it is important to explore new treatment options and improve the activity of existing antibiotics.
FOS, a phosphoenolpyruvate analog, is the recommended first-line antibiotic for uncomplicated urinary tract infections. Other drugs include trimethoprim-sulfamethoxazole and nitrofurantoin. Although they have been used for more than 40 years, the emergence of resistance in clinical isolates has been limited. Escherichia coli. Nevertheless, mutations especially in the transport system can cause spontaneous FOS resistance in UPEC. Antibiotic adjuvants have received significant attention over the years.
These products typically lack antimicrobial activity and can inhibit AMR or enhance the antimicrobial activity of certain drugs. CJ has long been the subject of research for its effects on urinary tract infections and is known for its anti-infective and anti-adhesion properties. However, its potential to modulate antibiotic activity is still incompletely understood.
Cranberry juice enhances fosfomycin across UPEC strains
In this study, researchers investigated whether CJ increases FOS activity on UPEC. First, they developed a method to test whether CJ can enhance the activity of UTI antibiotics, including FOS, cephalexin, ceftriaxone, ciprofloxacin, norfloxacin, amoxicillin-clavulanate, nitrofurantoin, and cotrimoxazole. The susceptibility (to antibiotics) of different UPEC strains was compared in the presence and absence of CJ.
The most significant and consistent effect of CJ was observed on FOS, which became the focus of subsequent analyses. We then used 32 UPEC strains to test their effects on FOS in a disk diffusion assay. CJ had a significant effect on FOS for 25 strains. Of note, two of the remaining strains were completely FOS resistant. We then tested a wider FOS concentration range (8 μg to 200 μg) for the four selected strains.
This effect increased with higher FOS concentrations. Resistant colonies were observed within the zone of growth inhibition around the antibiotic disc for all but two resistant strains. Virtually no colonies were present within the zone of inhibition on agar plates containing CJ. In contrast, colonies within the inhibition zone were easily detected even without CJ. Some resistant colonies found in the inhibition zone on CJ-containing plates were smaller and farther from the disc.
Next, the team examined changes in FOS resistance development. Cultures of the four strains were serially diluted and inoculated onto plates containing inhibitory levels of FOS, and bacterial counts on these plates were compared to bacterial counts on plates lacking FOS. Regardless of FOS concentration, the percentage of spontaneous resistance to FOS was significantly reduced in CJ-containing plates.
Notably, the use of CJ reduced emergence rates by five orders of magnitude, and no resistance was detected at higher FOS levels on CJ-containing plates. We then reisolated colonies from four UPEC strains that were resistant to FOS, including the colonies that appeared on CJ-containing plates. Their resistance profile was verified and resistant clones were subjected to whole genome sequencing.
Mutations were identified in various genes, including glycerol-3-phosphate transporter (glpT), pyruvate kinase 1 (pykF), and hexose 6-phosphate uptake transporter (uhpT). Remarkably, most of the clones on agar plates without CJ had mutations in pykF or glpT. The glpT mutation was observed in colonies isolated from CJ-free plates across strain backgrounds. In contrast, no glpT mutations were identified in colonies from plates containing CJ.
Instead, four of the six resistant clones isolated from CJ-containing plates had mutations in genes involved in the UhpT system. Further experiments showed that the UhpT system is the major transporter for FOS uptake in the presence of CJ. Furthermore, the presence of CJ effectively suppressed the expression of the GlpT system, the main mechanism of cell entry of FOS, while maintaining sufficient UhpT-mediated uptake for antibiotic entry.
Cranberry juice reprograms bacterial uptake to increase fosfomycin
This study demonstrated that CJ enhances FOS activity against UPEC. CJ modified the bacterial carbohydrate transport system to enhance FOS activity and suppress the emergence of resistance.
Importantly, these findings were obtained under in vitro conditions and cannot be directly extrapolated to clinical practice or cranberry juice intake in patients. Further studies are needed to identify the specific components of CJ responsible for the observed effects, reproduce these findings in physiologically relevant models, and investigate whether other antibiotics exhibit similar interactions.
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