Non-Antibiotic Drug Repositioning as an Alternative Antimicrobial Approach

Barbarossa, Alexia; Rosato, Antonio; Corbo, Filomena; Clodoveo, Maria Lisa; Fracchiolla, Giuseppe; Carrieri, Antonio; Carocci, Alessia

doi:10.3390/antibiotics11060816

Cited by 30 publications

(30 citation statements)

References 84 publications

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“…Synergy has been investigated and reported largely for multiple antibiotics (57). In the face of the emergence of multi-drug resistant organisms, antibiotic synergy with non-antibiotics has also gained interest (31,58) Most of the work has focused on the synergy between antibiotics and nonconventional antimicrobial strategies such as the use of bacteriophages, antimicrobial peptides, and small molecules, inhibiting vital bacterial processes (59)(60)(61)(62). Recently, there has also been considerable interest in repurposing non-antibiotic drugs for the purpose of infection prevention and management (63,64).…”

Section: Discussionmentioning

confidence: 99%

Synergistic use of anti-inflammatory ketorolac and gentamicin to target staphylococcal biofilms

Sekar,

Gil,

Tierney

et al. 2023

Preprint

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Background While antibiotics remain our primary tools against microbial infection, increasing antibiotic resistance (inherent and acquired) is a major detriment to their efficacy. A practical approach to maintaining or reversing the efficacy of antibiotics is the use of other commonly used therapeutics, which show synergistic antibacterial action with antibiotics. Here, we investigated the extent of antibacterial synergy between the antibiotic gentamicin and the anti-inflammatory ketorolac regarding the dynamics of biofilm growth, the rate of acquired resistance, and the possible mechanism of synergy. Methods Control (ATCC 12600, ATCC 35984) and clinical strains (L1101, L1116) of S. aureus and S. epidermidis with varying antibiotic susceptibility profiles were used in this study to simulate implant-material associated low-risk and high-risk biofilms in vitro. The synergistic action of gentamicin sulfate (GS) and ketorolac tromethamine (KT), against planktonic staphylococcal strains were determined using the fractional inhibitory concentration measurement assay. Nascent (6hr) and established (24hr) biofilms were grown on 316 stainless steel plates and the synergistic biofilm eradication activity was determined and characterized using adherent bacteria count, MBEC measurement for GS, gene expression of biofilm-associated genes, visualization by live/dead imaging, scanning electron microscopy, and bacterial membrane fluidity assessment. Results Gentamicin-ketorolac combination demonstrated synergistic antibacterial action against planktonic Staphylococci. Control and clinical strains showed distinct biofilm growth dynamics and an increase in biofilm maturity was shown to confer further resistance to gentamicin for both ‘low-risk’ and ‘high-risk’ biofilms. The addition of ketorolac enhanced the antibiofilm activity of gentamicin against acquired resistance in staphylococcal biofilms. Mechanistic studies revealed that the synergistic action of gentamicin-ketorolac interferes with biofilm morphology and subverts bacterial stress response altering bacterial physiology, membrane dynamics, and biofilm properties. Conclusion The results of this study have a significant impact on the local administration of antibiotics and other therapeutic agents commonly used in the prevention and treatment of orthopaedic infections. Further, these results warrant the study of synergy for the concurrent or sequential administration of non-antibiotic drugs for antimicrobial effect.

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Section: Discussionmentioning

confidence: 99%

Synergistic use of anti-inflammatory ketorolac and gentamicin to target staphylococcal biofilms

Sekar,

Gil,

Tierney

et al. 2023

Preprint

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“…9 Interestingly, finding new drugs with antibacterial effect from old drugs has become a costeffective method in recent years. 10 explore chemicals from the US Food and Drug Administration (FDA) approval drug library to inhibit the growth, biofilm formation, and persisters of S. aureus.…”

Section: ■ Introductionmentioning

confidence: 99%

“…However, the development of new antimicrobials often requires a long time, high investment costs, and huge risks . Interestingly, finding new drugs with antibacterial effect from old drugs has become a cost-effective method in recent years . Thus, this study aims to explore chemicals from the US Food and Drug Administration (FDA) approval drug library to inhibit the growth, biofilm formation, and persisters of S.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Inhibition of Growth, Biofilm Formation, and Persisters of Staphylococcus aureus by Pinaverium Bromide

et al. 2023

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Biofilm or persister cells formed by Staphylococcus aureus are closely related to pathogenicity. However, no antimicrobials exist to inhibit biofilm formation or persister cells induced by S. aureus in clinical practice. This study found that pinaverium bromide had antibacterial activity against S. aureus, with the MIC50/MIC90 at 12.5/25 μM, respectively. Pinaverium bromide (at 4 × MIC) showed a rapid bactericidal effect on S. aureus planktonic cells, and it was more effective (at least 1-log10 cfu/mL) than linezolid, vancomycin, and ampicillin at 4 h of the time-killing test. Pinaverium bromide (at 10 × MIC) significantly inhibited the formation of S. aureus persister cells (at least 3-log10 cfu/mL) than linezolid, vancomycin, and ampicillin at 24, 48, 72, 96, and 120 h of the time-killing test. Biofilm formation and adherent cells of S. aureus isolates were significantly inhibited by pinaverium bromide (at 1/2 or 1/4 × MICs). The fluorescence intensity of the membrane polarity of S. aureus increased with the treatment of pinaverium bromide (≥1 × MIC), and the MICs of pinaverium bromide increased by 4 times with the addition of cell membrane phospholipids, phosphatidyl glycerol and cardiolipin. The cell viabilities of human hepatocellular carcinoma cells HepG2 and Huh7, mouse monocyte-macrophage cells J774, and human hepatic stellate cells LX-2 were slightly inhibited by pinaverium bromide (<50 μM). There were 54 different abundance proteins detected in the pinaverium bromide-treated S. aureus isolate by proteomics analysis, of which 33 proteins increased, whereas 21 proteins decreased. The abundance of superoxide dismutase sodM and ica locus proteins icaA and icaB decreased. While the abundance of global transcriptional regulator spxA and Gamma-hemolysin component B increased. In conclusion, pinaverium bromide had an antibacterial effect on S. aureus and significantly inhibited the formation of biofilm and persister cells of S. aureus.

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“…When NSAIDs are associated with antibacterial drugs, the antimicrobial activity is usually enhanced [ 26 ]. In this sense, a formulation of IBP could include in its composition arginine, a prebiotic disruptor that affects the dynamic microbial interactions related to biofilm development [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial Activity and Cytotoxicity of Nonsteroidal Anti-Inflammatory Drugs against Endodontic Biofilms

Ferrer-Luque

Solana

Aguado³

et al. 2023

Antibiotics

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Persistent infections have become a challenge in dentistry because of growing antibiotic resistance. Nonsteroidal anti-inflammatory drugs (NSAIDs) appear to be a therapeutic alternative to control biofilm infection. The objective of this work is to evaluate the antimicrobial activity and cytotoxicity of sodium diclofenac (DCS), ibuprofen (IBP) and ibuprofen arginine (IBP-arginine) solutions against endodontic polymicrobial biofilms. Sterile radicular dentin blocks of 4 mm × 4 mm × 0.7 mm were used as substrate to grow biofilm. The dentin blocks were submerged into solutions for 5 min. The antimicrobial activity was evaluated by means of the adenosine triphosphate (ATP) assay and confocal laser scanning microscopy (CLSM). Fibroblasts 3T3-L1 (ECACC 86052701) were used to test the cytotoxicity of irrigating solutions. The antibiofilm effects determined by the ATP assay showed that 4% IBP-arginine solution exerted the highest antibiofilm activity, followed by 4% DCS and 4% IBP, with statistical differences among groups (p < 0.001). As for CLSM, 4% DCS and 4% IBP-arginine solutions gave the lowest viable cell percentages, without significant differences between them. Cytotoxicity results at 1/10 dilution were similar for all solutions. At 1/100 dilution, a 4% DCS solution obtained the lowest cell viability for both time periods assayed, 1 h and 24 h. The IBP-arginine group showed the highest cell viability at 24 h. In this preliminary study, in terms of antibiofilm activity and cytotoxicity, a mixed 4% IBP-arginine solution gave the most promising results. NSAID solutions could be recommendable drugs for endodontic disinfection procedures.

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Non-Antibiotic Drug Repositioning as an Alternative Antimicrobial Approach

Cited by 30 publications

References 84 publications

Synergistic use of anti-inflammatory ketorolac and gentamicin to target staphylococcal biofilms

Synergistic use of anti-inflammatory ketorolac and gentamicin to target staphylococcal biofilms

In Vitro Inhibition of Growth, Biofilm Formation, and Persisters of Staphylococcus aureus by Pinaverium Bromide

Antimicrobial Activity and Cytotoxicity of Nonsteroidal Anti-Inflammatory Drugs against Endodontic Biofilms

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