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1.  Antagonism of a Zinc Metalloprotease Using a Unique Metal-Chelating Scaffold: Tropolones as Inhibitors of P. aeruginosa Elastase†‡ 
Tropolone emerged from the screening of a chelator fragment library (CFL) as an inhibitor of the Zn2+-dependent virulence factor, Pseudomonas aeruginosa elastase (LasB). Based on this initial hit, a series of substituted tropolone-based LasB inhibitors was prepared, and a compound displaying potent activity in vitro and in a bacterial swarming assay was identified. Importantly, this inhibitor was found to be specific for LasB over other metalloenzymes, validating the usage of tropolone as a viable scaffold for identifying first-in-class LasB inhibitors.
doi:10.1039/c3cc41191e
PMCID: PMC3618488  PMID: 23482955
2.  Immunomodulation and the quorum sensing molecule 3-oxo-C12-homoserine lactone: The importance of chemical scaffolding for probe development† 
As a guide for chemical probe design, focused analogue synthetic studies were undertaken upon the lactone ring of 3-oxo-C12-homoserine lactone. We have concluded that hydrolytic instability of the heterocyclic ring is pivotal for its ability to modulate immune signaling and probe preparation was aligned with these findings.
doi:10.1039/c3cc38851d
PMCID: PMC3566768  PMID: 23328974
3.  3-Hydroxy-1-alkyl-2-methylpyridine-4(1H)-thiones: Inhibition of the Pseudomonas aeruginosa Virulence Factor LasB 
ACS medicinal chemistry letters  2012;3(8):668-672.
Bacterial resistance coupled to our current arsenal of antibiotics presents us with a growing threat to public health, thus warranting the exploration of alternative antibacterial strategies. In particular, the targeting of virulence factors has been regarded as a “second generation” antibiotic approach. In Pseudomonas aeruginosa, a Zn2+ metalloprotease virulence factor, LasB or P. aeruginosa elastase, has been implicated in the development of P. aeruginosa-related keratitis, pneumonia and burn infection. Moreover, the enzyme also plays a critical role in swarming and biofilm formation, both of which are processes that have been linked to antibiotic resistance. To further validate the importance of LasB in P. aeruginosa infection, we describe our efforts toward the discovery of non-peptidic small molecule inhibitors of LasB. Using identified compounds, we have confirmed the role that LasB plays in P. aeruginosa swarming and demonstrate the potential for LasB-targeted small molecules in studying antimicrobial resistant P. aeruginosa phenotypes.
doi:10.1021/ml300128f
PMCID: PMC3501683  PMID: 23181168
4.  3-Hydroxy-1-alkyl-2-methylpyridine-4(1H)-thiones: Inhibition of the Pseudomonas aeruginosa Virulence Factor LasB 
ACS Medicinal Chemistry Letters  2012;3(8):668-672.
Bacterial resistance coupled to our current arsenal of antibiotics presents us with a growing threat to public health, thus warranting the exploration of alternative antibacterial strategies. In particular, the targeting of virulence factors has been regarded as a “second generation” antibiotic approach. In Pseudomonas aeruginosa, a Zn2+ metalloprotease virulence factor, LasB or P. aeruginosa elastase, has been implicated in the development of P. aeruginosa-related keratitis, pneumonia, and burn infection. Moreover, the enzyme also plays a critical role in swarming and biofilm formation, both of which are processes that have been linked to antibiotic resistance. To further validate the importance of LasB in P. aeruginosa infection, we describe our efforts toward the discovery of nonpeptidic small molecule inhibitors of LasB. Using identified compounds, we have confirmed the role that LasB plays in P. aeruginosa swarming and demonstrate the potential for LasB-targeted small molecules in studying antimicrobial-resistant P. aeruginosa phenotypes.
doi:10.1021/ml300128f
PMCID: PMC3501683  PMID: 23181168
antibiotics; metalloprotease inhibitors; virulence factors; hydroxypyridinthiones
5.  Retraction: Stereochemical Insignificance Discovered in Acinetobacter baumannii Quorum Sensing 
PLoS ONE  2013;8(5):10.1371/annotation/1345f9b0-016e-4123-9e72-6ccc4fa17ba2.
doi:10.1371/annotation/1345f9b0-016e-4123-9e72-6ccc4fa17ba2
PMCID: PMC3655197  PMID: 23690906
6.  Retraction: Stereochemical Insignificance Discovered in Acinetobacter baumannii Quorum Sensing 
PLoS ONE  2013;8(4):10.1371/annotation/8f2ddf91-3499-4627-9a91-449b78465f9d.
doi:10.1371/annotation/8f2ddf91-3499-4627-9a91-449b78465f9d
PMCID: PMC3634625  PMID: 23853689
7.  cat-ELCCA: A Robust Method to Monitor the Fatty Acid Acyltransferase Activity of Ghrelin O-Acyltransferase (GOAT)** 
Assays armed with catalytic signal amplification have arisen as superior systems for ultrasensitive detection of analytes. Here we describe a conceptually new enzyme assay based on cat-ELISA, catalytic assay using enzyme-linked click chemistry assay (cat-ELCCA), where an enzyme-linked azide is utilized to arm the assay with catalytic fluorescence signal amplification. Using this assay technology, we have developed the first potentially high-throughput screen for the recently disclosed acyltransferase, ghrelin O-acyltransferase (GOAT).
doi:10.1002/anie.201003387
PMCID: PMC3485397  PMID: 20845345
alkynes; azides; enzymes; peptides
8.  A Multivalent Probe for AI-2 Quorum Sensing Receptors 
Journal of the American Chemical Society  2011;133(40):15934-15937.
Multivalency is a common principle in the recognition of cellular receptors, and multivalent agonists and antagonists have played a major role in understanding mammalian cell receptor biology. The study of bacterial cell receptors using similar approaches, however, has lagged behind. Herein we describe our efforts toward the development of a dendrimer-based multivalent probe for studying AI-2 quorum sensing receptors. From these studies, we have discovered a chemical probe specific for Lsr-type AI-2 quorum sensing receptors with the potential for enabling the identification of new bacterial species that utilize AI-2 as a quorum sensing signaling molecule.
doi:10.1021/ja207556d
PMCID: PMC3203215  PMID: 21913711
9.  Stereochemical Insignificance Discovered in Acinetobacter baumannii Quorum Sensing 
PLoS ONE  2012;7(5):e37102.
Stereochemistry is a key aspect of molecular recognition for biological systems. As such, receptors and enzymes are often highly stereospecific, only recognizing one stereoisomer of a ligand. Recently, the quorum sensing signaling molecules used by the nosocomial opportunistic pathogen, Acinetobacter baumannii, were identified, and the primary signaling molecule isolated from this species was N-(3-hydroxydodecanoyl)-l-homoserine lactone. A plethora of bacterial species have been demonstrated to utilize 3-hydroxy-acylhomoserine lactone autoinducers, and in virtually all cases, the (R)-stereoisomer was identified as the natural ligand and exhibited greater autoinducer activity than the corresponding (S)-stereoisomer. Using chemical synthesis and biochemical assays, we have uncovered a case of stereochemical insignificance in A. baumannii and provide a unique example where stereochemistry appears nonessential for acylhomoserine lactone-mediated quorum sensing signaling. Based on previously reported phylogenetic studies, we suggest that A. baumannii has evolutionarily adopted this unique, yet promiscuous quorum sensing system to ensure its survival, particularly in the presence of other proteobacteria.
doi:10.1371/journal.pone.0037102
PMCID: PMC3358330  PMID: 22629354
10.  Synthesis of “clickable” acylhomoserine lactone quorum sensing probes: unanticipated effects on mammalian cell activation 
Alkynyl- and azido-tagged 3-oxo-C12-acylhomoserine lactone probes have been synthesized to examine their potential utility as probes for discovering the mammalian protein target of the Pseudomonas aeruginosa autoinducer, 3-oxo-C12-acylhomoserine lactone. Although such substitutions are commonly believed to be quite conservative, from these studies, we have uncovered a drastic difference in activity between the alkynyl- and azido-modified compounds, and provide an example where such structural modification has proved to be much less than conservative.
doi:10.1016/j.bmcl.2010.11.122
PMCID: PMC3081916  PMID: 21190852
Acylhomoserine lactones; Click chemistry; Pseudomonas aeruginosa; Quorum sensing
11.  The Use of 3,5,4′-Tri-O-acetylresveratrol as a Potential Prodrug for Resveratrol Protects Mice from γ-Irradiation-Induced Death 
ACS Medicinal Chemistry Letters  2011;2(4):270-274.
Currently, no drugs are available to protect humans from γ-irradiation-induced death. Because reactive oxygen species are produced upon exposure to γ-irradiation and directly responsible for the resulting death, we hypothesized that antioxidants found in foodstuffs may provide a safe and potent means of antioxidant-dependent radioprotection. Here, we describe our studies investigating the radioprotective properties of resveratrol and 3,5,4′-tri-O-acetylresveratrol. Each of these natural antioxidants was found to protect live cells after γ-irradiation. In mice, the use of 3,5,4′-tri-O-acetylresveratrol with Cremophor EL was particularly effective, indicating that this natural antioxidant may be a leading candidate for radioprotective drug development.
doi:10.1021/ml100159p
PMCID: PMC3151144  PMID: 21826253
Antioxidants; resveratrol; 3,5,4′-tri-O-acetylresveratrol; radioprotection; Cremophor EL
12.  The Use of 3,5,4'-Tri-O-acetylresveratrol as a Potential Pro-drug for Resveratrol Protects Mice from γ-Irradiation–Induced Death 
ACS medicinal chemistry letters  2011;2(4):270-274.
Currently, no drugs are available to protect humans from γ-irradiation-induced death. Because reactive oxygen species are produced upon exposure to γ-irradiation and directly responsible for the resulting death, we hypothesized that antioxidants found in foodstuffs may provide a safe and potent means of antioxidant-dependent radioprotection. Here, we describe our studies investigating the radioprotective properties of resveratrol and 3,5,4'-tri-O-acetylresveratrol. Each of these natural antioxidants was found to protect live cells after γ-irradiation. In mice, the use of 3,5,4'-tri-O-acetylresveratrol with Cremophor EL was particularly effective, indicating that this natural antioxidant may be a leading candidate for radioprotective drug development.
doi:10.1021/ml100159p
PMCID: PMC3151144  PMID: 21826253
antioxidants; resveratrol; 3,5,4'-tri-O-acetylresveratrol; radioprotection; Cremophor EL
13.  Targeting the Wolbachia Cell Division Protein FtsZ as a New Approach for Antifilarial Therapy 
The use of antibiotics targeting the obligate bacterial endosymbiont Wolbachia of filarial parasites has been validated as an approach for controlling filarial infection in animals and humans. Availability of genomic sequences for the Wolbachia (wBm) present in the human filarial parasite Brugia malayi has enabled genome-wide searching for new potential drug targets. In the present study, we investigated the cell division machinery of wBm and determined that it possesses the essential cell division gene ftsZ which was expressed in all developmental stages of B. malayi examined. FtsZ is a GTPase thereby making the protein an attractive Wolbachia drug target. We described the molecular characterization and catalytic properties of Wolbachia FtsZ. We also demonstrated that the GTPase activity was inhibited by the natural product, berberine, and small molecule inhibitors identified from a high-throughput screen. Furthermore, berberine was also effective in reducing motility and reproduction in B. malayi parasites in vitro. Our results should facilitate the discovery of selective inhibitors of FtsZ as a novel anti-symbiotic approach for controlling filarial infection.
Note
The nucleotide sequences reported in this paper are available in GenBank™ Data Bank under the accession number wAlB-FtsZ (JN616286).
Author Summary
Filarial nematode parasites are responsible for a number of devastating diseases in humans and animals. These include lymphatic filariasis and onchocerciasis that afflict 150 million people in the tropics and threaten the health of over one billion. The parasites possess intracellular bacteria, Wolbachia, which are needed for worm survival. Clearance of these bacteria with certain antibiotics leads to parasite death. These findings have pioneered the approach of using antibiotics to treat and control filarial infections. In the present study, we have investigated the cell division process in Wolbachia for new drug target discovery. We have identified the essential cell division protein FtsZ, which has a GTPase activity, as an attractive Wolbachia drug target. We describe the molecular characterization and catalytic properties of the enzyme and demonstrate that the GTPase activity is inhibited by the natural product, berberine, and small molecule inhibitors identified from a high-throughput screen. We also found that berberine was effective in reducing motility and reproduction in B. malayi parasites in vitro. Our results should facilitate the discovery of selective inhibitors of FtsZ as a novel antibiotic approach for controlling filarial infection.
doi:10.1371/journal.pntd.0001411
PMCID: PMC3226453  PMID: 22140592
14.  Specific fluorogenic probes for ozone in biological and atmospheric samples 
Nature chemistry  2009;1:316-321.
Ozone exposure is a growing global health problem, especially in urban areas. While ozone in the stratosphere protects the earth from harmful ultraviolet light, tropospheric or ground-level ozone is toxic and can damage the respiratory tract. It has recently been shown that ozone may be produced endogenously in inflammation and antibacterial responses of the immune system; however, these results have sparked controversy owing to the use of a non-specific colorimetric probe. Here we report the synthesis of fluorescent molecular probes able to unambiguously detect ozone in both biological and atmospheric samples. Unlike other ozone-detection methods, in which interference from different reactive oxygen species is often a problem, these probes are ozone specific. Such probes will prove useful for the study of ozone in environmental science and biology, and so possibly provide some insight into the role of ozone in cells.
doi:10.1038/nchem.240
PMCID: PMC2904247  PMID: 20634904
16.  External compression-induced fracture patterning on the surface of poly(dimethylsiloxane) cubes and microspheres 
This paper describes a method for creating sub-micron surface patterns on cubes and microspheres. In this method, PDMS cubes and microspheres are exposed to oxygen plasma, which creates a very thin, hard, surface-modified layer on a compliant substrate. These are then compressed, causing the layer to crack in patterns dictated by the distribution of tensile stresses in the surface layer. Cracks with sub-micron widths were generated on 1 cm3 cubes and 800 µm-diameter microspheres, and the resulting crack patterns were observed. Finite-element simulations of the tensile stress distributions reveal that the fracture patterns arise from different mechanisms in the cubes and spheres. In particular, pattern formation is associated with frictional contact in the cubes; but not in the microspheres where geometrical effects associated with changes in the cross-sectional area along the axis lead to generation of tensile stress. These observations and analyses provide a foundation on which to predict and guide crack pattern formation on a wide variety of small 3D objects. In anticipation of future applications in materials science and biology, we demonstrate selective deposition of compounds into the cracks to make them functionally differentiable from the rest of the surface.
PMCID: PMC2772125  PMID: 19437776

Results 1-16 (16)