Sortase A: An ideal target for anti-virulence drug development

Cascioferro, Stella; Totsika, Makrina; Schillaci, Domenico

doi:10.1016/j.micpath.2014.10.007

Cited by 160 publications

(157 citation statements)

References 72 publications

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“…Sortases in pathogenic bacteria are frequently important virulence factors, as many of the proteins that they display have key roles in the infection process, such as promoting bacterial adhesion, nutrient acquisition, and the evasion and suppression of the immune response (Cascioferro, Totsika, & Schillaci, 2014; Schneewind & Missiakas, 2012, 2014; Siegel, Liu, & Ton-That, 2016; Spirig, Weiner, & Clubb, 2011). As a result, a significant amount of effort has been put forth to elucidate the mechanism of sortase-mediated catalysis and to discover small-molecule sortase inhibitors that could function as potent antiinfective agents (Bradshaw et al, 2015; Cascioferro et al, 2014; Clancy, Melvin, & McCafferty, 2010; Maresso & Schneewind, 2008; Suree, Jung, & Clubb, 2007). Moreover, sortases have been developed into valuable biochemical reagents to ligate distinct biomolecules together via a covalent peptide bond.…”

Section: Introductionmentioning

confidence: 99%

Sortase Transpeptidases: Structural Biology and Catalytic Mechanism

Jacobitz

Kattke

Wereszczynski

et al. 2017

Advances in Protein Chemistry and Structural Biology

114

142

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Gram-positive bacteria use sortase cysteine transpeptidase enzymes to covalently attach proteins to their cell wall and to assemble pili. In pathogenic bacteria sortases are potential drug targets, as many of the proteins that they display on the microbial surface play key roles in the infection process. Moreover, the Staphylococcus aureus Sortase A (SaSrtA) enzyme has been developed into a valuable biochemical reagent because of its ability to ligate biomolecules together in vitro via a covalent peptide bond. Here we review what is known about the structures and catalytic mechanism of sortase enzymes. Based on their primary sequences, most sortase homologs can be classified into six distinct subfamilies, called class A–F enzymes. Atomic structures reveal unique, class-specific variations that support alternate substrate specificities, while structures of sortase enzymes bound to sorting signal mimics shed light onto the molecular basis of substrate recognition. The results of computational studies are reviewed that provide insight into how key reaction intermediates are stabilized during catalysis, as well as the mechanism and dynamics of substrate recognition. Lastly, the reported in vitro activities of sortases are compared, revealing that the transpeptidation activity of SaSrtA is at least 20-fold faster than other sortases that have thus far been characterized. Together, the results of the structural, computational, and biochemical studies discussed in this review begin to reveal how sortases decorate the microbial surface with proteins and pili, and may facilitate ongoing efforts to discover therapeutically useful small molecule inhibitors.

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Section: Introductionmentioning

confidence: 99%

Sortase Transpeptidases: Structural Biology and Catalytic Mechanism

Jacobitz

Kattke

Wereszczynski

et al. 2017

Advances in Protein Chemistry and Structural Biology

114

142

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“…SrtA is thus a promising target for the design and development of novel anti-virulence drugs. 14,20 The crystal structure of SrtA has been described by a number of workers. For example, Ilangovan et al rst reported the crystal structure of a variant of S. aureus SrtA, in which the 59 amino acids at the N-terminus of the enzyme were truncated.…”

Section: Introductionmentioning

confidence: 99%

Recent progress in the development of sortase A inhibitors as novel anti-bacterial virulence agents

Guo

Cai

et al. 2015

RSC Adv.

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Sortase A (SrtA) is a membrane-associated enzyme responsible for the covalent anchoring of many virulent factors of Gram-positive bacteria onto the cell wall. It has been shown that SrtA plays a pivotal role in the pathogenic processes of bacterial infection. Additionally, SrtA is not essential for microbial growth and viability, and its inhibition does not therefore place pressure on bacteria to develop drug-resistant mechanism. As an extracellular membrane enzyme, it can more readily be targeted by drugs relevant to intracellular enzymes. SrtA is thus an excellent target for the design and development of novel anti-virulence drugs against the drug-resistant Gram-positive bacteria that have become a major worldwide health problem. A number of SrtA inhibitors have so far been identified by techniques such as the rational design of substrate mimetic inhibitors based on the structure of the enzyme and enzyme substrates, identification of novel inhibitors among natural products, the discovery and development of SrtA inhibitors via high-throughput, and in silico screening of small molecule libraries followed by structural optimization. The present article reviews the progress made recently in the development of SrtA inhibitors as new antibacterial agents using similar techniques.

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“…По мнению Stella Cascioferro [7], SrtA является идеальной мишенью для препаратов, направленных на подавление активности механизмов вирулентно-сти грамположительных бактерий.…”

Section: èíãèáèòîðû ñîðòàçû àunclassified

Етіологічна Терапія Бактеріальних Пневмоній Сьогодні Та В Майбутньому 3. Антибактеріальні Препарати, Що Розробляються

Abaturov¹,

Kryuchko²

2021

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Стрімке зростання антибіотикорезистентних бактеріальних штамів ставить на порядок денний необхідність розробки нових антибактеріальних засобів і перегляду рекомендацій етіологічного лікування бактеріальних інфекцій, у тому числі пневмоній. У даний час розробляються нові антибактеріальні препарати, що порушують біосинтез пептидоглікану, тейхоєвої і ліпотейхоєвої кислот, а також прикріплення факторів вірулентності до стінки бактерії. Нові молекули старих класів антибіотиків і представники нових класів антибіотиків, мішенями яких є ліпіди II і III, тейхоєва та ліпотейхоєва кислоти, аланін-рацемаза і сортаза A, в найближчому майбутньому стануть практичними інструментами в клінічній практиці. Цілі та механізми дії нових антибактеріальних сполук зумовлюють їх клінічну ефективність та перспективність у майбутніх стратегіях лікування інфекційних бактеріальних захворювань.

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Sortase A: An ideal target for anti-virulence drug development

Cited by 160 publications

References 72 publications

Sortase Transpeptidases: Structural Biology and Catalytic Mechanism

Sortase Transpeptidases: Structural Biology and Catalytic Mechanism

Recent progress in the development of sortase A inhibitors as novel anti-bacterial virulence agents

Етіологічна Терапія Бактеріальних Пневмоній Сьогодні Та В Майбутньому 3. Антибактеріальні Препарати, Що Розробляються

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