Covalent sortase A inhibitor ML346 prevents <i>Staphylococcus aureus</i> infection of <i>Galleria mellonella</i>

Guan, Xiang-Na; Zhang, Tao; Yang, Teng; Dong, Ze; Yang, Song; Lan, Lefu; Gan, Jianhua; Yang, Cai‐Guang

doi:10.1039/d1md00316j

Cited by 9 publications

(6 citation statements)

References 61 publications

(72 reference statements)

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“…Several compounds in this series were able to prevent invasion of Caco‐2 cells by L. monocytogenes at sub‐100 μM concentrations. From a slightly smaller screening of 4000 drug candidates and clinical drugs, a new irreversible SrtA inhibitor was identified [74] . ML346 (5, Figure 8) contains a barbituric acid and cinnamaldehyde scaffold and inhibits both S. aureus and S. pyogenes SrtA with IC 50 values of 0.37 μM and 1.37 μM, respectively.…”

Section: Small Molecule Srta Inhibitorsmentioning

confidence: 99%

The Complete Assessment of Small Molecule and Peptidomimetic Inhibitors of Sortase A Towards Antivirulence Treatment

Hintzen,

Abujubara,

Tietze

et al. 2024

Chemistry A European J

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This review covers the most recent advances in the development of inhibitors for the bacterial enzyme sortase A (SrtA). Sortase A (SrtA) is a critical virulence factor present ubiquitously in Gram‐positive bacteria of which many are considered pathogenic. Sortases are key enzymes regulating bacterial adherence to host cells, by anchoring extracellular matrix‐binding proteins to the bacterial outer cell wall. By targeting virulence factors, effective treatment can be achieved, without inducing antibiotic resistance to the treatment. All in all, this would lead to a more sustainable, long‐term approach to treating bacterial infections, including ones that display multiple resistance to current therapeutics. Currently, it appears there are many promising approaches available that have the potential to advance into further clinical development, with peptidomimetic and in vivo active small molecules among the most promising. There are currently no approved drugs on the market targeting SrtA, despite its promise, adding to the relevance of this review article, as it extends to the pharmaceutical industry additionally to academic researchers.

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Section: Small Molecule Srta Inhibitorsmentioning

confidence: 99%

The Complete Assessment of Small Molecule and Peptidomimetic Inhibitors of Sortase A Towards Antivirulence Treatment

Hintzen,

Abujubara,

Tietze

et al. 2024

Chemistry A European J

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“…Previously, we identified ML346 as a covalent inhibitor of both SaSrtA and SpSrtA. 48 The X-ray crystal structure of the ML346/SpSrtA ΔN81 complex revealed an extended pocket in SrtA that can add extra chemical space to ML346. Thus, we divided the ML346 structure into three parts for analog design (Figure 1).…”

Section: ■ Introductionmentioning

confidence: 97%

“…46,47 Recently, we resolved the X-ray crystal structure of ML346 covalently bound to Streptococcus pyogenes SrtA (SpSrtA), identifying a conjectural chemical space and facilitating the design and synthesis of novel SrtA inhibitors. 48 Herein, we report the rational design, synthesis, and structure−activity relationship (SAR) of ML346 analogs as covalent inhibitors for SaSrtA. ■ RESULTS AND DISCUSSION Design of ML346 Analogs.…”

Section: ■ Introductionmentioning

confidence: 99%

“…We previously identified sodium 3-(3-(pyridin-4-yl)-[1,2,4]triazolo[3,4- b ][1,3,4]thiadiazol-6-yl)benzenesulfonate ( 6e ) and tideglusib ( TD ) as noncovalent inhibitors of S. aureus SrtA ( Sa SrtA) that can attenuate virulence-related phenotypes in vitro and protect mice from MRSA infection. , Recently, we resolved the X-ray crystal structure of ML346 covalently bound to Streptococcus pyogenes SrtA ( Sp SrtA), identifying a conjectural chemical space and facilitating the design and synthesis of novel SrtA inhibitors . Herein, we report the rational design, synthesis, and structure–activity relationship (SAR) of ML346 analogs as covalent inhibitors for Sa SrtA.…”

Section: Introductionmentioning

confidence: 99%

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Structure-Guided Design, Synthesis, and Antivirulence Assessment of Covalent Staphylococcus aureus Sortase A Inhibitors

Yue,

Yuan,

et al. 2024

J. Med. Chem.

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Sortase A (SrtA) is a membrane-associated cysteine transpeptidase required for bacterial virulence regulation and anchors surface proteins to cell wall, thereby assisting biofilm formation. SrtA is targeted in antivirulence treatments against Gram-positive bacterial infections. However, the development of potent small-molecule SrtA inhibitors is constrained owing to the limited understanding of the mode of action of inhibitors in the SrtA binding pocket. Herein, we designed and synthesized a novel class of covalent SrtA inhibitors based on the binding mode detailed in the X-ray crystal structure of the ML346/Streptococcus pyogenes SrtA complex. ML346 analog Y40 exhibited 2-fold increased inhibitory activity on Staphylococcus aureus SrtA and showed superior inhibitory effects on biofilm formation in vitro. Y40 protected Galleria mellonella larvae fromS. aureusinfections in vivo while minimally attenuating staphylococcal growth in vitro. Our study indicates that the covalent SrtA inhibitor Y40 is an antivirulence agent that is effective againstS. aureusinfections.

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“…Given the dwindling supply of potent antibiotics, it is increasingly important to develop new methods of treating multidrugresistant MRSA infections 5 . To this end, developing antistaphylococcal agents, particularly those with a different mode of action, is urgently needed to provide future treatments for MRSA infections [6][7][8][9][10][11] .…”

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confidence: 99%

Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP

et al. 2022

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The emergence of methicillin-resistant Staphylococcus aureus isolates highlights the urgent need to develop more antibiotics. ClpP is a highly conserved protease regulated by ATPases in bacteria and in mitochondria. Aberrant activation of bacterial ClpP is an alternative method of discovering antibiotics, while it remains difficult to develop selective Staphylococcus aureus ClpP activators that can avoid disturbing Homo sapiens ClpP functions. Here, we use a structure-based design to identify (R)- and (S)-ZG197 as highly selective Staphylococcus aureus ClpP activators. The key structural elements in Homo sapiens ClpP, particularly W146 and its joint action with the C-terminal motif, significantly contribute to the discrimination of the activators. Our selective activators display wide antibiotic properties towards an array of multidrug-resistant staphylococcal strains in vitro, and demonstrate promising antibiotic efficacy in zebrafish and murine skin infection models. Our findings indicate that the species-specific activators of Staphylococcus aureus ClpP are exciting therapeutic agents to treat staphylococcal infections.

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Covalent sortase A inhibitor ML346 prevents Staphylococcus aureus infection of Galleria mellonella

Abstract: Covalent sortase A inhibitor ML346 prevents Galleria mellonella from Staphylococcus aureus infection by interfering in the transpeptidation activity of sortase A for anchoring surface proteins into staphylococci envelope.

Cited by 9 publications

References 61 publications

The Complete Assessment of Small Molecule and Peptidomimetic Inhibitors of Sortase A Towards Antivirulence Treatment

The Complete Assessment of Small Molecule and Peptidomimetic Inhibitors of Sortase A Towards Antivirulence Treatment

Structure-Guided Design, Synthesis, and Antivirulence Assessment of Covalent Staphylococcus aureus Sortase A Inhibitors

Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP

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