Meloxicam inhibits biofilm formation and enhances antimicrobial agents efficacy by Pseudomonas aeruginosa

Abstract

Microbial biofilms are communities of surface‐adhered cells enclosed in a matrix of extracellular polymeric substances. Bacterial cells in biofilm are 10~1,000‐fold more resistant to antimicrobials than the planktonic cells. Burgeoning antibiotic resistance in Pseudomonas aeruginosa biofilm has necessitated the development of antimicrobial agents. Here, we have investigated the antibiofilm effect of meloxicam against P. aeruginosa PAO1 and its potential mechanisms. Further, we have explored whether meloxicam could enhance the susceptibility of bacterial biofilms to treatment with conventional antimicrobials. Here, we found that meloxicam could significantly inhibit PAO1 biofilm formation in a dose‐dependent manner at the concentration without influence on planktonic cell growth. Meloxicam could also significantly inhibit the motilities, production of extracellular matrix, and expression of quorum sensing‐related genes and virulence factors of PAO1. Furthermore, synergistic interaction was observed when meloxicam combined with tetracycline, gentamicin, tobramycin, ciprofloxacin, ceftriaxone, ofloxacin, norfloxacin, ceftazidime, and DNase at subminimal inhibitory concentrations against PAO1 bioiflm. Collectively, our study lays the foundation for further investigation of repurposing meloxicam as a topical antibiofilm agent to treat P. aeruginosa biofilm‐related infections.

Drugs Repurposing for Multi-Drug Resistant Bacterial Infections

“…In turns, celecoxib and betamethasone have presented synergy with colistin, and with ceftazidime, erythromycin and ofloxacin against P. aeruginosa in vitro, respectively [19,76]. Similarly, meloxicam has been reported to be in vitro active alone and in combination with the sub-MIC of tetracycline, gentamicin, tobramycin, ciprofloxacin, ceftriaxone, ofloxacin, norfloxacin, ceftazidime against PAO1 strain, by inhibiting the biofilm formation [27]. Finally, GTS-21 has improved P. aeruginosa clearance in a murine model of ventilatorassociated pneumonia and reduced acute lung injury by enhancing macrophage function [39].…”

“…Different agents are promising both in vitro and in vivo candidates to be repositioned as antimicrobial agents to treat infections caused by MDR Gram-negative bacilli. A variety of drugs with different mechanisms of action and targets have been selected including: DNA, RNA and proteins inhibitors [16][17][18][19][20], QS regulators [15,17,[21][22][23][24][25], biofilm formation inhibitors and disruptors [26,27], drugs that interact with cell membrane [28][29][30], drugs that interact with iron metabolism [31][32][33][34][35], and host immune system modulators [36][37][38][39]. These drugs and their mechanisms of action against critical-priority pathogens (A. baumannii, P. aeruginosa and Enterobacterales) are summarized in Figure 1 and Table 1.…”

“…Anticancer and anti-inflammatory drugs that interact with DNA, RNA and proteins have been reported. Mitomycin C, used in several types of carcinomas such Binding to DNA during DNA synthesis and causes inhibition of its synthesis and function in P. aeruginosa and E. coli [18] Cisplatin Cancer Upregulation of the recA gene of P. aeruginosa, which is known to be important for DNA repair [20] Celecoxib Inflammation Inhibition of RNA, DNA, and protein synthesis in S. aureus [19] Quorum sensing 5-fluorouracil Solid tumors Inhibition of QS formation in P. aeruginosa [23,41] Raloxifene Breast cancer Binding to PhzB2 which is involved in the production of pyocyanin, a pigment related with virulence factor and QS signalling molecule in P. aeruginosa [24] Niclosamide Helminthiasis Production of the QS signaling molecules N-3-oxododecanoyl-homeserine lactone and Nbutanoyl-homoserine lactone in P. aeruginosa [15,25] Meloxicam Inflammation Interaction with active sites of the QS of P. aeruginosa [26] Metformin Diabetes Inhibition of QS system by bind to LasR by hydrogen bonding and electrostatic interaction and to rhlR by hydrogen bonding in P. aeruginosa [21] Biofilm formation 5-Fluorouracil Solid tumors Regulation of different genes involved in the biofilm formation by P. aeruginosa [41] Meloxicam Inflammation Decrease in the extracellular Psl, Pel, and alginate production by P. aeruginosa [26,27] Glatiramer acetate as the superficial vesical carcinoma [40], has shown activity against A. baumannii, P. aeruginosa and E. coli in vitro and in vivo [16][17][18]. Mitomycin C binds to DNA during DNA synthesis and causes inhibition of its synthesis and function in P. aeruginosa and E. coli [18].…”

“…Regarding the anthelmintic drugs, niclosamide, used for the treatment of helminthiasis, has been reported to inhibit QS in P. aeruginosa in Galleria mellonella model by hindering the cell's response and production of the QS signaling molecules as N-3-oxododecanoylhomeserine lactone and N-butanoyl-homoserine lactone [15,25]. Finally, meloxicam, a NSAID used to manage moderate-to-severe pain, and metformin, one of the most commonly prescribed oral hypoglycemic for treatment of type 2 diabetes, have been reported to interact with active sites and to inhibit the QS of P. aeruginosa, respectively [21,26,27]. Molecular docking study has shown that metformin could bind to LasR by hydrogen bonding and electrostatic interaction and to rhlR by hydrogen bonding only [21].…”

“…5-fluorouracil has been revealed to regulate different genes involved in the biofilm formation by P. aeruginosa [41]. More specifically, meloxicam has been reported to inhibit biofilm formation of P. aeruginosa by decreasing the extracellular Psl, Pel and alginate production, three vital biofilm exopolysaccharides in this pathogen [26,27]. Moreover, glatiramer acetate, a drug used in the treatment of multiple sclerosis, has also been shown to disrupt biofilm formation by GNB [42].…”