Sortase A Inhibitors: Recent Advances and Future Perspectives

Cascioferro, Stella; Raffa, Demetrio; Maggio, Benedetta; Raimondi, Maria Valeria; Schillaci, Domenico; Daidone, Giuseppe

doi:10.1021/acs.jmedchem.5b00779

Cited by 118 publications

(132 citation statements)

References 67 publications

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“…Sortase A (SrtA), a transpeptidase involved in the anchoring of surface proteins to the Gram-positive bacterial cell wall, plays a key role in bacterial adhesion, immune evasion and biofilm formation [12,13]. 1 H -Benzo[de][1,6]-naphthyridine alkaloid isoaaptamine, isolated from the marine sponge Aaptos aaptos [14], was reported to be a potent inhibitor of SrtA (IC 50 value of 3.7 µM). Topsentins and hamacanthins are representative examples of marine-derived compounds displaying SrtA inhibitory activity, in particular deoxytopsentin and 6′′-debromohamacanthin A, bis(indole)alkaloids isolated from the marine sponge Spongosorites sp., showed IC 50 values of 15.67 µM and 34.04 µM, respectively [15].…”

Section: Introductionmentioning

confidence: 99%

New Thiazole Nortopsentin Analogues Inhibit Bacterial Biofilm Formation

et al. 2018

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New thiazole nortopsentin analogues were conveniently synthesized and evaluated for their activity as inhibitors of biofilm formation of relevant Gram-positive and Gram-negative pathogens. All compounds were able to interfere with the first step of biofilm formation in a dose-dependent manner, showing a selectivity against the staphylococcal strains. The most active derivatives elicited IC50 values against Staphylococcus aureus ATCC 25923, ranging from 0.40–2.03 µM. The new compounds showed a typical anti-virulence profile, being able to inhibit the biofilm formation without affecting the microbial growth in the planktonic form.

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Section: Introductionmentioning

confidence: 99%

New Thiazole Nortopsentin Analogues Inhibit Bacterial Biofilm Formation

et al. 2018

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“…These sortases share a similar 8 stranded β-barrel-fold structure despite of sequence diversity. The Cys, His and Arg residues clustered at the center of a long cleft are identified as the key catalytic residues for these sortases [13]. The main enzymatic difference between Sa-SrtA and Sp-SrtA is their dependence on Ca 2+ .…”

Section: Introductionmentioning

confidence: 99%

“…This has been explained by the different residue arrangements of the β3/β4 loop and β6/β7 loop in SrtA structures [11, 12]. Over the past decade, useful investigations have been performed to identify inhibitors of Sa-SrtA to combat the alarming increase in antimicrobial resistance, and promising inhibitor compounds have been discovered [13]. The results show that natural products are good resource for SrtA inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Streptococcus suis sortase A is Ca2+ independent and is inhibited by acteoside, isoquercitrin and baicalin

et al. 2017

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Sortase A (SrtA) has long been recognized as an ideal drug target for therapeutic agents against Gram-positive pathogens. However, the SrtA of Streptococcus suis (Ss-SrtA), an important zoonotic agent, has not been studied. In this study, the enzymatic properties of Ss-SrtA were investigated, and inhibition of Ss-SrtA by natural products was evaluated. Ss-SrtA was expressed and purified. The purified recombinant Ss-SrtA had maximal activity at pH 6.0–7.5, 45°C, and showed a Km of 6.7 μM for the hydrolysis of substrate abz-LPATG-dnp. Different from Staphylococcus aureus SrtA (Sa-SrtA) which is stimulated by Ca2+, Ss-SrtA was observed to be Ca2+ independent. Structural analysis showed that salt bridges formed between K111 and D180 in Ss-SrtA replaced the function of Ca2+ in Sa-SrtA to stabilize the substrate-binding cleft. Site-directed mutagenesis identified H126, C192 and R200 as the key residues of Ss-SrtA active site. To discover potential inhibitors, the percent inhibition of sortase activity by natural products was measured. Among these selected natural products, acteoside, isoquercitrin and baicalin were discovered as novel SrtA inhibitors, with IC50 values of 36.3 ± 1.3 μM, 100.0 ± 1.3 μM and 85.4 ± 1.5 μM, respectively. The inhibitory effects of these three natural products were further confirmed on endogenous Sa-SrtA. Using a previously established S. aureus model with a fluorescent-labeled Sa-SrtA substrate, acteoside, isoquercitrin, and baicalin showed 86%, 28% and 45% inhibition on endogenous Sa-SrtA activity, respectively. Overall, these findings shed new light on enzymatic properties, Ca2+-independent catalytic mechanism and potential inhibitors of Ss-SrtA.

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“…Agents targeting bacterial virulence factors without interfering on bacterial viability have the advantage to disarm pathogens without killing them, with a consequent lower pressure in the rise of antibiotic resistant strains (Cascioferro et al 2014b(Cascioferro et al , 2015. The use of antimicrobial peptides (AMPs) to control infections impair the development of drug resistance due to the multiplicity of their biological activities (Parachin and Franco 2014).…”

Section: Introductionmentioning

confidence: 99%

A peptide from human β thymosin as a platform for the development of new anti-biofilm agents for Staphylococcus spp. and Pseudomonas aeruginosa

Schillaci

Spinello

Cusimano

et al. 2016

World J Microbiol Biotechnol

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Conventional antibiotics might fail in the treatment of biofilm-associated infections causing infection recurrence and chronicity. The search for antimicrobial peptides has been performed with the aim to discover novel anti-infective agents active on pathogens in both planktonic and biofilm associated forms. The fragment 9-19 of human thymosin β4 was studied through 1 μs MD simulation. Two main conformations of the peptide were detected, both constituted by a central hydrophobic core and by the presence of peripheral charged residues suggesting a possible mechanism of interaction with two models of biological membranes, related to eukaryotic or bacterial membrane respectively. In addition, the peptide was chemically synthesized and its antimicrobial activity was tested in vitro against planktonic and biofilm form of a group of reference strains of Staphylococcus spp. and one P. aeruginosa strain. The human thymosin β4 fragment EIEKFDKSKLK showed antibacterial activity against staphylococcal strains and Pseudomonas aeruginosa ATCC 15442 at concentrations from 12.5 to 6.2 mg/ml and inhibited biofilm formation at sub-inhibitory concentrations (3.1-0.75 mg/ml). The activity of the fragment in inhibiting biofilm formation, could be due to the conformations highlighted by the MD simulations, suggesting its interaction with the bacterial membrane. Human thymosin β4 fragment can be considered a promising lead compound to develop novel synthetic or recombinant derivatives with improved pharmaceutical potential.

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Sortase A Inhibitors: Recent Advances and Future Perspectives

Cited by 118 publications

References 67 publications

New Thiazole Nortopsentin Analogues Inhibit Bacterial Biofilm Formation

New Thiazole Nortopsentin Analogues Inhibit Bacterial Biofilm Formation

Streptococcus suis sortase A is Ca2+ independent and is inhibited by acteoside, isoquercitrin and baicalin

A peptide from human β thymosin as a platform for the development of new anti-biofilm agents for Staphylococcus spp. and Pseudomonas aeruginosa

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