From large networks to small molecules

Sharom, Jeffrey R.; Bellows, David S.; Tyers, Mike

doi:10.1016/j.cbpa.2003.12.007

Cited by 93 publications

(74 citation statements)

References 76 publications

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“…Our data show that it is possible to effectively kill bacteria by turning their own biological responses against them, namely, by using drug combinations that induce the cell to transition to an alternative form and then exploiting the inherent weaknesses of that form. Drug combinations are commonly used in medicine to enhance the effectiveness of existing antibiotics (24) and represent a promising avenue for the development of new treatments (27)(28)(29) with reduced rates of resistance (30). In this study, we have shown that combinations of meropenem with the AMPs LL-37 or nisin are potently bactericidal against P. aeruginosa at concentrations where each drug alone has negligible bactericidal activity.…”

Section: Discussionmentioning

confidence: 79%

Rapid Conversion of Pseudomonas aeruginosa to a Spherical Cell Morphotype Facilitates Tolerance to Carbapenems and Penicillins but Increases Susceptibility to Antimicrobial Peptides

Monahan

Turnbull

Osvath

et al. 2014

Antimicrob Agents Chemother

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bThe Gram-negative human pathogen Pseudomonas aeruginosa tolerates high concentrations of ␤-lactam antibiotics. Despite inhibiting the growth of the organism, these cell wall-targeting drugs exhibit remarkably little bactericidal activity. However, the mechanisms underlying ␤-lactam tolerance are currently unclear. Here, we show that P. aeruginosa undergoes a rapid en masse transition from normal rod-shaped cells to viable cell wall-defective spherical cells when treated with ␤-lactams from the widely used carbapenem and penicillin classes. When the antibiotic is removed, the entire population of spherical cells quickly converts back to the normal bacillary form. Our results demonstrate that these rapid population-wide cell morphotype transitions function as a strategy to survive antibiotic exposure. Taking advantage of these findings, we have developed a novel approach to efficiently kill P. aeruginosa by using carbapenem treatment to induce en masse transition to the spherical cell morphotype and then exploiting the relative fragility and sensitivity of these cells to killing by antimicrobial peptides (AMPs) that are relatively inactive against P. aeruginosa bacillary cells. This approach could broaden the repertoire of antimicrobial compounds used to treat P. aeruginosa and serve as a basis for developing new therapeutic agents to combat bacterial infections. P seudomonas aeruginosa is a major human pathogen and a leading cause of hospital-acquired infections. P. aeruginosa infections are difficult to eradicate and are often fatal, which is in part due to the organism's high intrinsic resistance to a variety of different antimicrobials (1). The mechanisms underlying intrinsic antibiotic resistance in P. aeruginosa are largely well understood. However, an important and as yet unexplained observation is the ability of P. aeruginosa to survive in the presence of high concentrations of the cell wall-targeting ␤-lactam antibiotics.␤-Lactams are a broad class of antibiotics that include penicillin derivatives, cephalosporins, monobactams, and carbapenems. They are the most widely used group of antibiotics in the world (2) and mediate bacterial killing primarily by inhibiting the enzymes, known as penicillin-binding proteins (PBPs), that catalyze the formation of peptidoglycan cross-links in the bacterial cell wall (3). ␤-Lactam drugs typically exhibit bactericidal activity against susceptible organisms (4), and this is often associated with changes in bacterial morphology and the formation of spherical or filamentous cells that are prone to lysis (3,(5)(6)(7)(8).Interestingly, despite inhibiting cell growth, ␤-lactams have been found to have very little bactericidal activity against P. aeruginosa (9-13). This intrinsic tolerance of ␤-lactams likely accounts for the fact that when P. aeruginosa infections are treated, optimal microbiological outcomes occur when ␤-lactam concentrations are maintained at 4 to 6.6 times the MIC throughout the majority of the dosing period (13). Furthermore, ␤-lactam tolerance by P. aer...

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Section: Discussionmentioning

confidence: 79%

Rapid Conversion of Pseudomonas aeruginosa to a Spherical Cell Morphotype Facilitates Tolerance to Carbapenems and Penicillins but Increases Susceptibility to Antimicrobial Peptides

Monahan

Turnbull

Osvath

et al. 2014

Antimicrob Agents Chemother

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“…Synthetic lethal interactions often are difficult to predict, and genome-wide screens in model organisms indicate that they can be difficult to rationalize even a posteriori, as is true also in the work described here (4,5). It nonetheless is intriguing that MET, CDK6, and MAP2K1 have been linked previously to kidney cancer biology.…”

Section: Discussionmentioning

confidence: 84%

“…Synthetic lethality has been well studied in the budding yeast Saccharomyces cerevisiae, in which only 20% of the genes are individually essential and synthetic lethal interactions are common among the remaining 80% (4)(5)(6). Many of these synthetic lethal interactions would have been difficult to predict a priori and were revealed only by unbiased genetic screens.…”

mentioning

confidence: 99%

Kinase requirements in human cells: III. Altered kinase requirements inVHL−/− cancer cells detected in a pilot synthetic lethal screen

Bommi-Reddy

Almeciga

Sawyer

et al. 2008

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

137

117

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Clear cell renal carcinomas are the most common form of kidney cancer and frequently are linked to biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. The VHL gene product, pVHL, has multiple functions including directing the polyubiquitylation of the HIF transcription factor. We screened 100 shRNA vectors, directed against 88 kinases, for their ability to inhibit the viability of VHL؊/؊ renal carcinoma cells preferentially compared with isogenic cells in which pVHL function was restored. shRNAs for ''hits'' identified in the primary screen were interrogated in secondary screens that included shRNA titration studies. Multiple shRNAs against CDK6, MET, and MAP2K1 (also known as MEK1) preferentially inhibited the viability of 786-O and RCC4 VHL؊/؊ cells compared with their wild-type pVHL-reconstituted counterparts. The sensitivity of pVHL-proficient cells to these shRNAs was not restored upon HIF activation, suggesting that loss of an hypoxia-inducible factor (HIF)-independent pVHL function formed the basis for selectivity. A small-molecule Cdk4/6 inhibitor displayed enhanced activity against VHL؊/؊ renal carcinoma cells, suggesting that in some cases hits from shRNA screens such as described here might translate into therapeutic targets.essential kinases ͉ shRNA screens ͉ VHL ͉ kidney cancer ͉ therapeutics

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“…Multi-targeting therapy can overcome toxicity and other side effects associated with high doses of single-target drugs by countering biological compensation (11,37). As a tubulin and HSP90 dual targeting inhibitor, another important feature of CDBT is its low toxicity.…”

Section: Low Toxicity Of Cdbt In Vitro and In Vivomentioning

confidence: 99%

P-Glycoprotein-Evading Anti-tumor Activity of a Novel Tubulin and HSP90 Dual Inhibitor in a Non-small-cell Lung Cancer Model

et al. 2014

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Abstract. P-glycoprotein (P-gp)-induced drug resistance is a major road block for successful cancer chemotherapy. Through phenotypic screening, the compound 2-(2-chlorophenylimino)-5-(4-dimethylaminobenzylidene)thiazolidin-4-one (CDBT) was discovered to have potent antitumor activity in P-gp over-expressing drug-resistant non-small-cell lung cancer (NSCLC) H460 TaxR cells. Here, we report mechanistic investigations of the P-gp-evading anti-tumor activity of CDBT. CDBT is evidently not a P-gp substrate and escapes the P-gp efflux pump. As a novel microtubule and heat shock protein 90 (HSP90) dual targeting inhibitor, CDBT causes the destabilization of microtubules and degradation of HSP90 client proteins CRAF-1 and ERBB2, resulting in cell cycle arrest at the G2/M phase and apoptosis. Furthermore, CDBT effectively inhibits tumor growth by 60.4% relative to the vehicle control after intraperitoneal administration at 30 mg/kg for 11 days and shows no toxicity in normal tissues in the NSCLC H460 TaxR xenograft mouse model. Our data suggest a novel drug discovery strategy to combat P-gp over-expressing drug-resistant NSCLC cancer cells with a single therapeutic agent.[Supplementary materials: available only at http://dx

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From large networks to small molecules

Cited by 93 publications

References 76 publications

Rapid Conversion of Pseudomonas aeruginosa to a Spherical Cell Morphotype Facilitates Tolerance to Carbapenems and Penicillins but Increases Susceptibility to Antimicrobial Peptides

Rapid Conversion of Pseudomonas aeruginosa to a Spherical Cell Morphotype Facilitates Tolerance to Carbapenems and Penicillins but Increases Susceptibility to Antimicrobial Peptides

Kinase requirements in human cells: III. Altered kinase requirements inVHL−/− cancer cells detected in a pilot synthetic lethal screen

P-Glycoprotein-Evading Anti-tumor Activity of a Novel Tubulin and HSP90 Dual Inhibitor in a Non-small-cell Lung Cancer Model

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