Identification of a Novel Benzimidazole That Inhibits Bacterial Biofilm Formation in a Broad-Spectrum Manner

Sambanthamoorthy, Karthik; Gokhale, Ankush A.; Lao, Weiwei; Parashar, Vijay; Neiditch, Matthew B.; Semmelhack, M. F.; Lee, Ilsoon; Waters, Christopher M.

doi:10.1128/aac.00583-11

Cited by 89 publications

(62 citation statements)

References 48 publications

(47 reference statements)

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“…Sambanthamoorthy et al recently identified a novel benzimidazole that inhibits bacterial biofilm formation (14). In their study, a small-molecule screen identified a benzimidazole that prevented biofilm formation in multiple bacterial pathogens, including S. aureus and P. aeruginosa.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Biofilm Formation by Esomeprazole in Pseudomonas aeruginosa and Staphylococcus aureus

Singh

Arora

Alam

et al. 2012

Antimicrob Agents Chemother

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Staphylococcus aureus and Pseudomonas aeruginosa are common nosocomial pathogens responsible for biofilm-associated infections. Proton pump inhibitors (PPI), such as esomeprazole, may have novel antimicrobial properties. The objective of this study was to assess whether esomeprazole prevents sessile bacterial growth and biofilm formation and whether it may have synergistic killing effects with standard antibiotics. The antibiofilm activity of esomeprazole at 0.25 mM was tested against two strains each of S. aureus and P. aeruginosa. Bacterial biofilms were prepared using a commercially available 96-peg-plate Calgary biofilm device. Sessile bacterial CFU counts and biomass were assessed during 72 hours of esomeprazole exposure. The killing activities after an additional 24 hours of vancomycin (against S. aureus) and meropenem (against P. aeruginosa) treatment with or without preexposure to esomeprazole were also assessed by CFU and biomass analyses. P. aeruginosa and S. aureus strains exposed to esomeprazole displayed decreased sessile bacterial growth and biomass (P < 0.001, each parameter). After 72 h of exposure, there was a 1-log 10 decrease in the CFU/ml of esomeprazole-exposed P. aeruginosa and S. aureus strains compared to controls (P < 0.001). After 72 h of exposure, measured absorbance was 100% greater in P. aeruginosa control strains than in esomeprazole-exposed strains (P < 0.001). Increased killing and decreased biomass were observed for esomeprazoletreated bacteria compared to untreated controls exposed to conventional antibiotics (P < 0.001, each parameter). Reduced biofilm growth after 24 h was visibly apparent by light micrographs for P. aeruginosa and S. aureus isolates exposed to esomeprazole compared to untreated controls. In conclusion, esomeprazole demonstrated an antibiofilm effect against biofilm-producing S. aureus and P. aeruginosa. P roton pump inhibitors (PPI) have been shown to have novel antibacterial properties (9, 15). Against Helicobacter pylori, benzimadazole PPI have been shown to have direct antimicrobial effects (15). PPI have also been shown to have other effects on microbiologic activity, including inhibition of urease (12). In 2005, an in vitro study investigated the antibiofilm properties of PPI benzimidazoles against oral streptococci (10). The results showed that the additions of omeprazole and lansoprazole had a significant effect on Streptococcus mutans biofilms, a common organism found in the human oral flora. However, antibiofilm effects of PPI on other bacteria have not been well studied.The two most common nosocomial organisms responsible for catheter-related infections, Pseudomonas aeruginosa and Staphylococcus aureus, have a natural tendency to adhere to catheter surfaces and form biofilms, which prevent eradication of these organisms by the immune system or with antibiotics (16). Theoretically, prevention of biofilm formation by these bacteria could prevent catheter-related infections among hospitalized patients and lead to a major improvement in the care of thes...

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Section: Discussionmentioning

confidence: 99%

Inhibition of Biofilm Formation by Esomeprazole in Pseudomonas aeruginosa and Staphylococcus aureus

Singh

Arora

Alam

et al. 2012

Antimicrob Agents Chemother

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“…Static biofilm formation was determined using MBEC plates as described previously (37). MBEC plates were grown for 8 h with gentle rocking before biofilms of V. cholerae were determined by staining with crystal violet.…”

Section: Methodsmentioning

confidence: 99%

Quantification of high-specificity cyclic diguanylate signaling

Massie¹,

Reynolds²,

Koestler³

et al. 2012

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

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141

143

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Cyclic di-GMP (c-di-GMP) is a second messenger molecule that regulates the transition between sessile and motile lifestyles in bacteria. Bacteria often encode multiple diguanylate cyclase (DGC) and phosphodiesterase (PDE) enzymes that produce and degrade c-di-GMP, respectively. Because of multiple inputs into the c-di-GMP-signaling network, it is unclear whether this system functions via high or low specificity. High-specificity signaling is characterized by individual DGCs or PDEs that are specifically associated with downstream c-di-GMP-mediated responses. In contrast, low-specificity signaling is characterized by DGCs or PDEs that modulate a general signal pool, which, in turn, controls a global c-di-GMPmediated response. To determine whether c-di-GMP functions via high or low specificity in Vibrio cholerae, we correlated the in vivo c-di-GMP concentration generated by seven DGCs, each expressed at eight different levels, to the c-di-GMP-mediated induction of biofilm formation and transcription. There was no correlation between total intracellular c-di-GMP levels and biofilm formation or gene expression when considering all states. However, individual DGCs showed a significant correlation between c-di-GMP production and c-di-GMP-mediated responses. Moreover, the rate of phenotypic change versus c-di-GMP concentration was significantly different between DGCs, suggesting that bacteria can optimize phenotypic output to c-di-GMP levels via expression or activation of specific DGCs. Our results conclusively demonstrate that c-di-GMP does not function via a simple, low-specificity signaling pathway in V. cholerae.signaling specificity | systems biology

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“…The highthroughput screen to identify compounds that interfere with c-di-GMP signaling was previously described (38). Briefly, a V. cholerae reporter strain containing two plasmids was utilized.…”

Section: Methodsmentioning

confidence: 99%

“…The details of the screen have been previously described (38). To identify DGC inhibitors, we grew V. cholerae cells containing a transcriptional reporter that is induced by c-di-GMP in the presence of 66,000 compounds/natural-product extracts at the Center for Chemical Genomics at the University of Michigan.…”

Section: Small-molecule Screenmentioning

confidence: 99%

Identification of Small Molecules That Antagonize Diguanylate Cyclase Enzymes To Inhibit Biofilm Formation

Sambanthamoorthy

Sloup

Parashar

et al. 2012

Antimicrob Agents Chemother

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125

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c Bacterial biofilm formation is responsible for numerous chronic infections, causing a severe health burden. Many of these infections cannot be resolved, as bacteria in biofilms are resistant to the host's immune defenses and antibiotic therapy. New strategies to treat biofilm-based infections are critically needed. Cyclic di-GMP (c-di-GMP) is a widely conserved second-messenger signal essential for biofilm formation. As this signaling system is found only in bacteria, it is an attractive target for the development of new antibiofilm interventions. Here, we describe the results of a high-throughput screen to identify small-molecule inhibitors of diguanylate cyclase (DGC) enzymes that synthesize c-di-GMP. We report seven small molecules that antagonize these enzymes and inhibit biofilm formation by Vibrio cholerae. Moreover, two of these compounds significantly reduce the total concentration of c-di-GMP in V. cholerae, one of which also inhibits biofilm formation by Pseudomonas aeruginosa in a continuous-flow system. These molecules represent the first compounds described that are able to inhibit DGC activity to prevent biofilm formation.

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Identification of a Novel Benzimidazole That Inhibits Bacterial Biofilm Formation in a Broad-Spectrum Manner

Cited by 89 publications

References 48 publications

Inhibition of Biofilm Formation by Esomeprazole in Pseudomonas aeruginosa and Staphylococcus aureus

Inhibition of Biofilm Formation by Esomeprazole in Pseudomonas aeruginosa and Staphylococcus aureus

Quantification of high-specificity cyclic diguanylate signaling

Identification of Small Molecules That Antagonize Diguanylate Cyclase Enzymes To Inhibit Biofilm Formation

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