Pharmacophore-Based Repositioning of Approved Drugs as Novel <i>Staphylococcus aureus</i> NorA Efflux Pump Inhibitors

Astolfi, Andrea; Felicetti, Tommaso; Iraci, Nunzio; Manfroni, Giuseppe; Massari, Serena; Pietrella, Donatella; Tabarrini, Oriana; Kaatz, Glenn W.; Barreca, Maria Letizia; Sabatini, Stefano; Cecchetti, Violetta

doi:10.1021/acs.jmedchem.6b01439

Cited by 57 publications

(54 citation statements)

References 43 publications

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“…The lack of information regarding specific interactions between substrates and EPIs with NorA also makes it difficult to rationally design potent inhibitors with computational methods. However, the LBDD approach has been applied successfully in the case of 2‐phenylquinoline derivatives as NorA inhibitors by Sabatini et al They used a library of the most potent NorA EPIs described in the literature to build a pharmacophore model in an attempt to find their common characteristics. The generated pharmacophore model revealed four chemical features of potent NorA EPIs: one H‐bond acceptor, one positive charge, one aromatic ring and one other aromatic ring or hydrophobic region …”

Section: Future Perspectivesmentioning

confidence: 99%

“…However, the LBDD approach has been applied successfully in the case of 2-phenylquinoline derivatives as NorA inhibitors by Sabatini et al 196,261 They used a library of the most potent NorA EPIs described in the literature to build a pharmacophore model in an attempt to find their common characteristics. The generated pharmacophore To develop high potency inhibitors, it is most appropriate to start from small molecules that possess physicochemical properties according to the "rule of 3" (molecular weight ≤ 300, clogP ≤ 3, rotatable bonds ≤ 3, H-bond donors ≤ 3, H-bond acceptors ≤ 3, PSA ≤ 3), since they are suitable for the process of optimization.…”

Section: Future Perspectivesmentioning

confidence: 99%

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Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

Lamut

Mašič

Kikelj

et al. 2019

Medicinal Research Reviews

141

116

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Bacterial infections are an increasingly serious issue worldwide. The inability of existing therapies to treat multidrug‐resistant pathogens has been recognized as an important challenge of the 21st century. Efflux pumps are important in both intrinsic and acquired bacterial resistance and identification of small molecule efflux pump inhibitors (EPIs), capable of restoring the effectiveness of available antibiotics, is an active research field. In the last two decades, much effort has been made to identify novel EPIs. However, none of them has so far been approved for therapeutic use. In this article, we explore different structural families of currently known EPIs for multidrug resistance efflux systems in the most extensively studied pathogens (NorA in Staphylococcus aureus, AcrAB‐TolC in Escherichia coli, and MexAB‐OprM in Pseudomonas aeruginosa). Both synthetic and natural compounds are described, with structure‐activity relationship studies and optimization processes presented systematically for each family individually. In vitro activities against selected test strains are presented in a unifying manner for all the EPIs described, together with the most important toxicity, pharmacokinetic and in vivo efficacy data. A critical evaluation of lead‐likeness characteristics and the potential for clinical development of the most promising inhibitors of the three efflux systems is described. This overview of EPIs is a good starting point for the identification of novel effective antibacterial drugs.

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Section: Future Perspectivesmentioning

confidence: 99%

Section: Future Perspectivesmentioning

confidence: 99%

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

Lamut

Mašič

Kikelj

et al. 2019

Medicinal Research Reviews

141

116

View full text Add to dashboard Cite

show abstract

“…EtBr will remain in the bacteria, and will emit fluorescence whose intensity will be stable over time. On the other hand, if the compounds do not inhibit the efflux pump, the fluorescence intensity will decrease over time, due to EtBr extrusion by the NorA efflux pump …”

Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of 2‐Aminothiophene Derivatives as Staphylococcus aureus Efflux Pump Inhibitors

et al. 2020

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2-aminothiophene derivatives (2AT) in which the thiophene ring is fused with a cycloalkyl or a N-acylated piperidine ring by positions 5 and 6 and carrying a 3-carbethoxy group were synthesized and their bacterial growth and enzyme inhibitory effects against efflux proteins of Staphylococcus aureus leading to resistance to fluoroquinolones and erythromycin (ERY) were investigated. Compounds that most effectively decreases the minimum inhibitory concentrations (MICs) of ciprofloxacin (CIP) were assayed for their dose and time effects on the accumulation and efflux of ethidium bromide (EtBr) in the SA-1 strain. None of the compounds displayed antibacterial activity however, three derivatives carrying 2-amino, 2-aminoacetyl and 2-aminotrifluoroacetyl group enhanced the activity of CIP and ERY by 8-and 16-fold, respectively, and were able to restore the sensitivity of resistant strains, acting as typical efflux pump inhibitors (EPIs). The 2-aminoacetyl and 2-aminotrifluoroacetyl derivatives and two other piperidinyl 2-aminotrifluoroacetyl derivatives increased EtBr accumulation in a dose-and timedependent manner, and one of them was also able to inhibit the EtBr efflux. Taken together, these results represent an important advance in the development of new EPIs, and demonstrate that 2AT represent a good scaffold for developing new antibiotic adjuvants.[a] Dr.

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“…Multidrug resistant efflux pumps are recognized as important components of resistance in both Gram-positive and Gram-negative bacteria, which reduce the intracellular concentration of drug compounds through active extrusion from the cell (Fern andez & Hancock, 2012;Du et al, 2018). In S. aureus, several multidrug efflux pumps, such as NorA, NorB and MepA, have been described that are associated with resistance to antibiotics, and NorA is the most important and well characterized efflux pump (Holler et al 2012;Astolfi et al, 2017;Felicetti et al, 2017;Felicetti et al, 2018). It is reported that the stable hydrogen bonding interactions between ginsenoside Rh2 (G-Rh2) and Gln51/Asn340/ Ser226 residues at active binding site in the central cavity of protein was responsible for the inhibition of NorA pump, thus G-Rh2 could be used as an inhibitor of the NorA efflux pump to restore susceptibility to common antibiotics in multiple drug resistant (MDR) bacteria (Zhang et al, 2014;Shriram et al, 2018;Kumar et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

PLGA microsphere-based composite hydrogel for dual delivery of ciprofloxacin and ginsenoside Rh2 to treat Staphylococcus aureus -induced skin infections

et al. 2020

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When antibiotic-resistant pathogenic bacteria pose a high threat to human health, bacterial multidrug efflux pumps become major contributors to the high-level antibiotic resistance in most microorganisms. Since traditional antibiotics are still indispensable currently, we report a dual drug delivery system to maximize the antibacterial efficacy of antibiotics by inhibiting efflux pumps in bacteria before their exposure to antibiotics. In this research, a microsphere/hydrogel composite was constructed from ciprofloxacin (Cip)-loaded poly (lactic-co-glycolic acid) (PLGA) microspheres and ginsenoside Rh2 (G-Rh2) dispersed thermo-sensitive hydrogel to treat skin infections. In vitro drug release studies indicated that while G-Rh2 in hydrogel presented a faster and short-term release manner to rapidly inhibit the NorA efflux pumps, Cip showed a sustained and long-term release behavior to provide a local high concentration gradient for facilitating drug percutaneous penetration. The combination of Cip and G-Rh2 demonstrated a high degree of synergism against both methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), hence significantly improving their in vitro antibacterial activity and efficiency. Moreover, the antibacterial performance of the microsphere/hydrogel composite with a sequential release profile is superior to that of other formulations in mouse model of MRSA skin infections, indicating its great potential to treat antibiotic-resistant skin infections.

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Pharmacophore-Based Repositioning of Approved Drugs as Novel Staphylococcus aureus NorA Efflux Pump Inhibitors

Cited by 57 publications

References 43 publications

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

Synthesis and Evaluation of 2‐Aminothiophene Derivatives as Staphylococcus aureus Efflux Pump Inhibitors

PLGA microsphere-based composite hydrogel for dual delivery of ciprofloxacin and ginsenoside Rh2 to treat Staphylococcus aureus -induced skin infections

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