Proton pump inhibitors act synergistically with fluconazole against resistant Candida albicans

Abstract

the incidence of resistant Candida isolates, especially Candida albicans, has increased continuously. To overcome the resistance, research on antifungal agent sensitizers has attracted considerable attention. Omeprazole and lansoprazole were found to inhibit the growth of sensitive C. albicans and hyphae formation in a high dose, respectively. This study aimed to determine the interactions of common clinically proton pump inhibitors (PPIs) and fluconazole both in vitro and in vivo and to further explore the possible mechanisms. In vitro, the tested PPIs all acted synergistically with fluconazole against both resistant C. albicans planktonic cells and biofilms preformed for ≤12 h with the minimum inhibitory concentration of fluconazole decreased from >512 μg/mL to 1-4 μg/mL. In vivo, PPIs plus fluconazole prolonged the survival rate of infected Galleria mellonella larvae by twofold compared with that for the fluconazole monotherapy group and significantly reduced the tissue damage of infected larvae. Mechanism studies showed that PPIs significantly suppressed efflux pump activity, which is the common resistance mechanism of C. albicans, and significantly inhibited the virulence factors: phospholipase activity and morphology switching. These findings will provide new insights into antifungal agent discovery and potential approaches for the treatment of candidiasis caused by resistant C. albicans. The incidence of invasive fungal infections has increased continuously, especially those caused by Candida species 1,2. Candida species can cause superficial infection of the skin, mouth, or mucous membranes and can also cause invasive infection, such as candidemia and biofilm-related infection 3. In Candida infections, C. albicans is still the most commonly isolated strain. Data from the Prospective Antifungal Therapy Alliance registry showed that among the 7526 fungi isolated from 6807 invasive fungal infections, the isolation rate of Candida species was highest (n = 5526, 73.4%), and C. albicans accounted for 47.8% of its isolation rate 4. Owing to its great efficacy and low toxicity, fluconazole (FLC) has been extensively used in clinical practice to prevent and treat candidiasis. However, along with the increased in frequency of infections and extensive use of FLC, drug-resistant strains have frequently emerged 5,6. To overcome fungal resistance, research on antifungal sensitizers has attracted considerable attention. Proton pump inhibitors (PPIs) inhibit the H + /K +-ATPase in the cell membrane and have become the first choice in the treatment of acid-related diseases 7,8. PPIs with a wide range of clinical applications include omeprazole (OME), lansoprazole (LAN), pantoprazole (PTP), rabeprazole (RAB), esomeprazole (ESO) and ilaprazole (ILA). OME was found to cure acute oesophageal necrosis and candidal oesophageal when it was combined with FLC in the clinic 9-11. Studies on the antifungal activity of PPIs found that LAN and OME at a dose of >600 µg/ mL could inhibit the growth of sensitive C. albicans and hyphae fo...

Understanding How Microorganisms Respond to Acid pH Is Central to Their Control and Successful Exploitation

“…The identification of these regulatory proteins/pathways could represent a novel cohort of possible therapeutic targets, particularly important with the global rise in antimicrobial resistance. Acid pH also modulates the interaction between pathogens and antimicrobials ( Danby et al, 2012 ; Yang et al, 2017 ; Lourenço et al, 2019 ; Lu et al, 2020 ). The possibility of exploring molecules whose activity can be potentiated at low pH (e.g., organic acids) as treatments, either alone or in combination with antifungals/antibiotics, seems worth pursuing, with some preliminary results showing that SCFA at low pH can increase the efficacy of azoles and antibiotics ( Yang et al, 2017 ; Li et al, 2018 ).…”

Techniques for the Assessment of In Vitro and In Vivo Antifungal Combinations

“…Combinations of antifungals with antibiotics have also been tested and gave similar results [123][124][125][126]. Finally, other studies have used this model to demonstrate the synergistic interaction between fluconazole and other drugs against C. albicans [127][128][129][130][131]. Many studies have used G. mellonella as a model for the evaluation of antifungal combinations against Cryptococcus spp.…”

Galleria mellonella for the Evaluation of Antifungal Efficacy against Medically Important Fungi, a Narrative Review

“…Antifungal combinations against Candida spp. have also been explored in the G. mellonella model [18,[35][36][37][38][39][40][41][42][43][44]73].…”

“…Several other studies (Table 2) used G. mellonella to demonstrate synergistic interactions between antifungals (mainly fluconazole) and other drugs against C. albicans [35,[37][38][39][40]43,44,73]. The partner drugs were anti-inflammatory compounds such as dexamethasone [43] and licofelone [40], Dpenicillamine, a heavy metal chelator [39], harmine, an alkaloid with multiple pharmacological properties [37], ambroxol, a mucolytic drug [38], antivirals such as ribavirin [44], proton-pump inhibitors [73], or Hsp-90 (a molecular chaperone implicated in cellular response to stress) inhibitors [35].…”