A new antibiotic with potent activity targets MscL

Iscla, Irene; Wray, Robin; Blount, Paul; Larkins-Ford, Jonah; Conery, Annie L.; Ausubel, Frederick M.; Ramu, Soumya; Kavanagh, Angela M.; Huang, Johnny X.; Blaskovich, Mark A. T.; Cooper, Matthew A.; Obregón-Henao, Andrés; Orme, Ian M.; Tjandra, Edwin S.; Stroeher, Uwe H.; Brown, Melissa H.; Macardle, Peter J.; Holst, Nick van; Tong, Chee Ling; Slattery, Ashley; Gibson, Christopher T.; Raston, Colin L.; Boulos, Ramiz A.

doi:10.1038/ja.2015.4

Cited by 50 publications

(60 citation statements)

References 31 publications

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“…Pioneering works demonstrated that MscL can be converted into a light-activated nanovalve useful for the triggered release of compounds in liposomes (13)(14)(15). Recent studies suggest that the open pore of MscL permits entry of streptomycin and could potentially serve as a target for antimicrobial agents (16,17).…”

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confidence: 99%

Mechanical coupling of the multiple structural elements of the large-conductance mechanosensitive channel during expansion

Guo

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The prokaryotic mechanosensitive channel of large conductance (MscL) is a pressure-relief valve protecting the cell from lysing during acute osmotic downshock. When the membrane is stretched, MscL responds to the increase of membrane tension and opens a nonselective pore to about 30 Å wide, exhibiting a large unitary conductance of ∼3 nS. A fundamental step toward understanding the gating mechanism of MscL is to decipher the molecular details of the conformational changes accompanying channel opening. By applying fusionprotein strategy and controlling detergent composition, we have solved the structures of an archaeal MscL homolog from Methanosarcina acetivorans trapped in the closed and expanded intermediate states. The comparative analysis of these two new structures reveals significant conformational rearrangements in the different domains of MscL. The large changes observed in the tilt angles of the two transmembrane helices (TM1 and TM2) fit well with the helix-pivoting model derived from the earlier geometric analyses based on the previous structures. Meanwhile, the periplasmic loop region transforms from a folded structure, containing an ω-shaped loop and a short β-hairpin, to an extended and partly disordered conformation during channel expansion. Moreover, a significant rotating and sliding of the N-terminal helix (N-helix) is coupled to the tilting movements of TM1 and TM2. The dynamic relationships between the N-helix and TM1/TM2 suggest that the N-helix serves as a membraneanchored stopper that limits the tilts of TM1 and TM2 in the gating process. These results provide direct mechanistic insights into the highly coordinated movement of the different domains of the MscL channel when it expands. mechanosensitive channel | gating mechanism | crystal structure | membrane protein | osmoregulation

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confidence: 99%

Mechanical coupling of the multiple structural elements of the large-conductance mechanosensitive channel during expansion

Guo

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Ramizol is the first member of a new antibiotic family that selectively targets the mechanosensitive ion channel of large conductance (MscL) in bacteria [123] and possesses potent antioxidant properties as well [124]. In a hamster model of CDI orally administered Ramizol conferred lower 28-day survival than vancomycin (57% vs. 86%), and its spore-clearing capacity was also inferior to that of vancomycin (29–57% vs. 100%) [125].…”

Section: Antibiotics and Non-antibiotic Anticlostridial Agentsmentioning

confidence: 99%

A Review of Experimental and Off-Label Therapies for Clostridium difficile Infection

2016

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In spite of increased awareness and the efforts taken to optimize Clostridium difficile infection (CDI) management, with the limited number of currently available antibiotics for C. difficile the halt of this increasing epidemic remains out of reach. There are, however, close to 80 alternative treatment methods with controversial anti-clostridial efficacy or in experimental phase today. Indeed, some of these therapies are expected to become acknowledged members of the recommended anti-CDI arsenal within the next few years. None of these alternative treatment methods can respond in itself to all the major challenges of CDI management, which are primary prophylaxis in the susceptible population, clinical cure of severe cases, prevention of recurrences, and forestallment of asymptomatic C. difficile carriage and in-hospital spread. Yet, the greater the variety of treatment choices on hand, the better combination strategies can be developed to reach these goals in the future. The aim of this article is to provide a comprehensive summary of these experimental and currently off-label therapeutic options.

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“…5–7 The end point of the assay is to measure the survival of MRSA-infected worms that have been treated with test compounds. This liquid infection assay was used to identify antibacterial hits from a library of 21,472 pre-selected compounds provided by Boehringer-Ingelheim GmbH (BI).…”

Section: Identification Of Pspc As a Hit Compound That Prolongs Survimentioning

confidence: 99%

Antibacterial properties of 3-(phenylsulfonyl)-2-pyrazinecarbonitrile

Rajaraman

Jayamani

Majed

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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The emergence of multidrug-resistant bacterial strains has heightened the need for new antimicrobial agents based on novel chemical scaffolds that are able to circumvent current modes of resistance. We recently developed a whole-animal drug-screening methodology in pursuit of this goal and now report the discovery of 3-(phenylsulfonyl)-2-pyrazinecarbonitrile (PSPC) as a novel antibacterial effective against resistant nosocomial pathogens. The minimum inhibitory concentrations (MIC) of PSPC against Staphylococcus aureus and Enterococcus faecium were 4 μg/ml and 8 μg/ml, respectively, whereas the MICs were higher against the Gram-negative bacteria Klebsiella pneumoniae (64 μg/ml), Acinetobacter baumannii (32 μg/ml), Pseudomonas aeruginosa (>64 μg/ml), and Enterobacter spp. (>64 μg/ml). However, co-treatment of PSPC with the efflux pump inhibitor phenylalanine arginyl β-naphthylamide (PAβN) or with sub-inhibitory concentrations of the lipopeptide antibiotic polymyxin B reduced the MICs of PSPC against the Gram-negative strains by >4-fold. A sulfide analogue of PSPC (PSPC-1S) showed no antibacterial activity, whereas the sulfoxide analogue (PSPC-6S) showed identical activity as PSPC across all strains, confirming structure-dependent activity for PSPC and suggesting a target-based mechanism of action. PSPC displayed dose dependent toxicity to both Caenorhabditis elegans and HEK-293 mammalian cells, culminating with a survival rate of 16% (100 μg/mL) and 8.5% (64 μg/mL), respectively, at the maximum tested concentration. However, PSPC did not result in hemolysis of erythrocytes, even at a concentration of 64 μg/mL. Together these results support PSPC as a new chemotype suitable for further development of new antibiotics against Gram-positive and Gram-negative bacteria.

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A new antibiotic with potent activity targets MscL

Cited by 50 publications

References 31 publications

Mechanical coupling of the multiple structural elements of the large-conductance mechanosensitive channel during expansion

Mechanical coupling of the multiple structural elements of the large-conductance mechanosensitive channel during expansion

A Review of Experimental and Off-Label Therapies for Clostridium difficile Infection

Antibacterial properties of 3-(phenylsulfonyl)-2-pyrazinecarbonitrile

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