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PubMed2005

Overexpression of the multidrug efflux pumps MexCD-OprJ and MexEF-OprN is associated with a reduction of type III secretion in Pseudomonas aeruginosa.

The Pseudomonas aeruginosa genome contains several different multidrug resistance (MDR) efflux pumps. Overproduction of these pumps reduces susceptibility to a variety of antibiotics. Some recently published works have analyzed the effect of the overproduction of MDR efflux pumps on bacterial virulence. Here we have studied the effect of overproduction of the efflux pumps MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY on type III secretion (T3S) in P. aeruginosa. The type III secretion system (T3SS) is used by P. aeruginosa to deliver toxins directly into the cytoplasm of the host cell. Our data indicate that overexpression of either MexCD-OprJ or MexEF-OprN is associated with the impairment of T3S in P. aeruginosa. No effect on overexpression of either MexAB-OprM or MexXY was detected. The observed defect in T3S was due to a lack of expression of genes belonging to the T3SS regulon. Transcription of this regulon is activated by ExsA in response to environmental signals. Overexpression of this transcriptional regulator complemented the defect in T3S observed in the MexCD-OprJ- and MexEF-OprN-overproducing strains. Taken together, these results suggest that overproduction of either MexCD-OprJ or MexEF-OprN is associated with a reduction in the transcription of the T3SS regulon due to the lack of expression of the exsA gene, encoding the master regulator of the system. The relevance of potential metabolic and quorum-sensing imbalances due to overexpression of MDR pumps associated with this phenotype is also discussed.

Bacterial Outer Membrane Proteins↗

PubMed2005

ATR/TEM8 is highly expressed in epithelial cells lining Bacillus anthracis' three sites of entry: implications for the pathogenesis of anthrax infection.

Anthrax is a disease caused by infection with spores from the bacteria Bacillus anthracis. These spores enter the body, where they germinate into bacteria and secrete a tripartite toxin that causes local edema and, in systemic infections, death. Recent studies identified the cellular receptor for anthrax toxin (ATR), a type I membrane protein. ATR is one of the splice variants of the tumor endothelial marker 8 (TEM8) gene. ATR and TEM8 are identical throughout their extracellular and transmembrane sequence, and both proteins function as receptors for the toxin. ATR/TEM8 function and expression have been associated with development of the vascular system and with tumor angiogenesis. TEM8 is selectively upregulated in endothelial cells during blood vessel formation and tumorigenesis. However, selective expression of TEM8 in endothelial cells contradicts the presumably ubiquitous expression of the receptor. To resolve this controversial issue, we evaluated the distribution of ATR/TEM8 in a variety of tissues. For this purpose, we generated and characterized a novel anti-ATR/TEM8 polyclonal antibody. Here, we show that this novel antibody recognizes all three ATR/TEM8 isoforms, which are widely and differentially expressed in various tissue types. We found that ATR/TEM8 expression is not only associated with tumor endothelial cells, as previously described. Indeed, ATR/TEM8 is highly and selectively expressed in the epithelial cells lining those organs that constitute the anthrax toxin's sites of entry, i.e., the lung, the skin, and the intestine. In fact, we show that ATR/TEM8 is highly expressed in the respiratory epithelium of the bronchi of the lung and is particularly abundant in the ciliated epithelial cells coating the bronchi. Furthermore, immunostaining of skin biopsies revealed that ATR/TEM8 is highly expressed in the keratinocytes of the epidermis. Finally, we show that the epithelial cells lining the small intestine strongly express ATR/TEM8 isoforms. This is the first demonstration that the ATR/TEM8 protein is highly expressed in epithelial cells, which represent the primary location for bacterial invasion. These results suggest that the ATR/TEM8 expression pattern that we describe here is highly relevant for understanding the pathogenesis of anthrax infection.

Amino Acid Sequence↗

PubMed1991

Adenosine 3',5'-monophosphate and phorbol ester induce transforming growth factor-beta 1 messenger ribonucleic acid levels in choriocarcinoma cells.

Transforming growth factor-beta 1 (TGF-beta 1), a regulator of growth and differentiation of many cell types, has previously been purified from the human placenta, and the messenger (m) RNA is abundantly expressed there. We found that the approximate 2.5-kilobase TGF-beta 1 mRNA is expressed in JEG-3 human choriocarcinoma cells, which have been widely used as a model system for studying the regulation of trophoblast hormone secretion. Cholera toxin (CT) elevates the cellular levels of the second messenger cAMP and increases the secretion of CG and steroids in these cells, thus being a potent inducer of trophoblast-differentiated functions. We show that CT also stimulates TGF-beta 1 mRNA levels in JEG-3 cells in a concentration- and time-dependent manner as studied by Northern and dot blotting. The maximal effect (about 5-fold increase above basal levels) occurs within 12-48 h of induction with a CT concentration of 1.0 ng/ml. The cell-permeable cAMP-analog 8-bromo-cAMP stimulates the accumulation of TGF-beta 1 mRNA in JEG-3 cells as well. Furthermore, this cAMP analog also induces TGF-beta 1 mRNA levels in normal cultured term placental cytotrophoblasts. 12-O-Tetradecanoyl phorbol-13-acetate, an active phorbol ester protein kinase C regulator and inducer of TGF-beta 1 mRNA in many cells, increases TGF-beta 1 mRNA accumulation in JEG-3 cells with a similar time course as cAMP analogs but to a lesser extent. Human HT-1080 fibrosarcoma and A-549 lung carcinoma cells exhibit up-regulation of TGF-beta 1 mRNA in response to TGF-beta 1 itself, but we show that activation of the cAMP-dependent pathway does not affect TGF-beta 1 mRNA levels in these cells. Cycloheximide, an inhibitor of protein synthesis, prevents the effect of CT and 12-O-tetradecanoyl phorbol-13-acetate on TGF-beta 1 mRNA expression in JEG-3 cells, suggesting that a protein mediator may be involved in the transduction of their effects. Our finding of a cAMP-dependent induction pathway for TGF-beta 1 mRNA expression in JEG-3 cells provides a new mechanism for the regulation of the synthesis of this ubiquitous growth and differentiation factor and suggests that TGF-beta 1 may have a role in trophoblast differentiation.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1997

Effects of calcium channel blockade on intestinal fluid secretion: sites of action.

Most intestinal secretagogues, including cholera toxin, evoke fluid secretion in part by activating the enteric nervous system (ENS). The enterotoxins that, due to size, cannot pass the intestinal epithelial lining have been proposed to activate the ENS via the release of amines/peptides from the intestinal endocrine cells. It has been shown that calcium channel blockers of the L-type attenuate intestinal fluid secretion. This study was performed on rat jejunal segments to elucidate where calcium channel antagonists interact with the secretory nervous reflex(es) of the ENS. In vivo, net fluid transport, transmural potential difference (PD) and luminal release of serotonin from the enterochromaffin cells were monitored before and after exposing the intestinal mucosa to cholera toxin (20 microg/mL) or the calcium ionophore A23187 (0.5 mM). In vitro, the effects of transmural electrical field stimulation (EFS) on short circuit current (SCC) was investigated using the Ussing chamber method. Cholera toxin and A23187 evoked a net fluid secretion, an increased PD and an augmented luminal release of 5-HT. These effects were markedly attenuated by giving the calcium channel blocker nifedipine i.v. (5.75 micromol kg(-1) body wt). On the other hand, nifedipine (0.02 mM) had no significant effect on the increased SCC caused by EFS in vitro. The results obtained in the in vivo experiments suggest that the nifedipine markedly attenuates the initial event in cholera toxin- and A23187-induced secretion, the release of amines and probably also of peptides from the intestinal endocrine cells. The in vitro experiments seem to exclude an effect of the calcium channel blockade on the efferent part of the secretory nervous reflex.

Animals↗

PubMed2000

Functional analysis of the type III secretion system in enteropathogenic Escherichia coli O157:H45.

A mass outbreak of Escherichia coli O157:H45 was first reported in Japan in 1998. This pathogen was classified as an enteropathogenic E. coli (EPEC) O157 because it was characterized by the Shiga toxin gene (stx)-negative and bundle-forming pilus (bfp) gene-positive genotypes. In this study, we investigated the type III secretion system in EPEC O157. Although no type III secreted proteins, Esps (E. colisecreted proteins), in EPEC O157:H45 were detectable in culture supernatant, secreted proteins were induced by the introduction of an EPEC plasmid-encoded regulator, per. In further contrast to EHEC O157:H7, EPEC O157:H45 triggered the accumulation of tyrosine phosphorylated proteins beneath the adherent bacteria. These results suggest that regulation of the type III secretion apparatus and host signal transduction events between E. coli O157:H45 and O157:H7 are completely different.

Adhesins, Bacterial↗

PubMedDate not supplied

[Types of secretion and regulation of the functional activity of molecules associated with the pathogenicity of Enterobacteriaceae].

Five types of nonhomologous systems of the export of protein molecules, known to exist in pathogenic bacteria, are characterized. The described secretion systems take part in the synthesis of not only toxic proteins, but also different adhesins and hydrolytic enzymes. In the export of Enterobacteriaceae toxins secretion types I, II, III and V are of importance. Characteristics of Sec-dependence at the stage of transport through the cytoplasmic membrane is the key sign in their differentiation. The functional activity of bacterial toxins and the level of toxigenicity expression are finely regulated signs, mediated by external signals. The systems for their regulation are relatively few in number and rather conservative. As shown in this study, the regulation of pathogenicity expression has no specific mechanisms. Moreover, it is regulated by common systems and mechanisms for the regulation of usual physiological processes.

Adhesins, Bacterial↗

PubMed2000

Neurokinin 1 and 2 receptors mediate cholera toxin secretion in rat jejunum.

BACKGROUND & AIMS: Substance P, a member of the tachykinin family, is a prosecretory neuropeptide distributed widely throughout the enteric nervous system. Implicated in inflammatory states, its role in enterotoxigenic water and electrolyte secretion is unclear. We assessed the effect of substance P antagonists and neurokinin receptor antagonists on cholera toxin-, Escherichia coli heat-labile enterotoxin (LT)-, and heat-stable enterotoxin (STa)-induced water secretion in an in vivo rat jejunal perfusion model. METHODS: Anesthetized adult male Wistar rats were pretreated with substance P antagonists (D-Pro(2), D-Trp(79), substance P, 0.1-3.0 mg/kg; or CP 96,345/4, 0.3-3 mg/kg) or neurokinin (NK)-1 (sendide, 1.0 mg/kg), NK-2 (GR83074, 1.0 mg/kg), or NK-3 ([Trp(7),betaAla(8)]NKA(4-10), 1.0 mg/kg) receptor antagonists. In a subgroup, extrinsic sensory afferents were ablated by pretreatment with capsaicin. Jejunal perfusion, with a plasma electrolyte solution containing a nonabsorbable marker, was undertaken after exposure to cholera toxin (25 microg), LT (25 microg), STa (200 microg/L), or saline. RESULTS: Cholera toxin-induced water and electrolyte secretion was inhibited by the substance P antagonists and the NK-1 and NK-2 receptor antagonists, but not by the NK-3 receptor antagonist or by pretreatment with capsaicin. Neither LT- nor STa-induced secretions were affected by the pretreatments. CONCLUSIONS: Prosecretory pathways involving NK-1 and NK-2 receptors specifically mediate the actions of cholera toxin in the small intestine.

Animals↗

PubMed2001

Identification of the cellular receptor for anthrax toxin.

The tripartite toxin secreted by Bacillus anthracis, the causative agent of anthrax, helps the bacterium evade the immune system and can kill the host during a systemic infection. Two components of the toxin enzymatically modify substrates within the cytosol of mammalian cells: oedema factor (OF) is an adenylate cyclase that impairs host defences through a variety of mechanisms including inhibiting phagocytosis; lethal factor (LF) is a zinc-dependent protease that cleaves mitogen-activated protein kinase kinase and causes lysis of macrophages. Protective antigen (PA), the third component, binds to a cellular receptor and mediates delivery of the enzymatic components to the cytosol. Here we describe the cloning of the human PA receptor using a genetic complementation approach. The receptor, termed ATR (anthrax toxin receptor), is a type I membrane protein with an extracellular von Willebrand factor A domain that binds directly to PA. In addition, a soluble version of this domain can protect cells from the action of the toxin.

Amino Acid Sequence↗

PubMed2000

A genomic approach to the understanding of Xylella fastidiosa pathogenicity.

Xylella fastidiosa is a fastidious, xylem-limited bacterium that causes several economically important plant diseases, including citrus variegated chlorosis (CVC). X. fastidiosa is the first plant pathogen to have its genome completely sequenced. In addition, it is probably the least previously studied of any organism for which the complete genome sequence is available. Several pathogenicity-related genes have been identified in the X. fastidiosa genome by similarity with other bacterial genes involved in pathogenesis in plants, as well as in animals. The X. fastidiosa genome encodes different classes of proteins directly or indirectly involved in cell-cell interactions, degradation of plant cell walls, iron homeostasis, anti-oxidant responses, synthesis of toxins, and regulation of pathogenicity. Neither genes encoding members of the type III protein secretion system nor avirulence-like genes have been identified in X. fastidiosa.

Bacterial Toxins↗

PubMed1989

Galanin inhibits insulin secretion by direct interference with exocytosis.

Electrically permeabilized RINm5F cells were used to study whether galanin inhibits insulin secretion distally to the generation of soluble second messengers. Ca2+-induced insulin secretion was inhibited by the neuropeptide in a dose-dependent manner. Galanin appears to act via a G-protein as pertussis toxin treatment abolished the effect. GTP (100 microM), GDP (100 microM) and a low dose of GTP gamma S (10 microM) did not affect galanin-mediated inhibition of secretion. In contrast, at 100 microM, GTP gamma S attenuated and GDP beta S abolished the effect of the peptide. We conclude that galanin inhibits exocytosis directly by a mechanism involving a G-protein.

Calcium↗

PubMed2006

Anthrax oedema toxin induces anthrax toxin receptor expression in monocyte-derived cells.

Bacillus anthracis, the causative agent of anthrax, secretes two bipartite toxins that help the bacterium evade the immune system and contribute directly to pathogenesis. Both toxin catalytic moieties, lethal factor (LF) and oedema factor (OF), are internalized into the host-cell cytosol by a third factor, protective antigen (PA), which binds to cellular anthrax toxin receptors (ANTXRs). Oedema factor is an adenylate cyclase that impairs host defences by raising cellular cAMP levels. Here we demonstrate that oedema toxin (PA + OF) induces an increase in ANTXR expression levels in macrophages and dendritic cells resulting in an increased rate of toxin internalization. Furthermore, we show that increases in ANTXR mRNA levels depends on the ability of OF to increase cAMP levels, is mediated through protein kinase A-directed signalling and is monocyte-lineage-specific. To our knowledge, this is the first report of a bacterial toxin inducing host target cells to increase toxin receptor expression.

Adenylyl Cyclases↗

PubMed2005

Microarray-based detection of genetic heterogeneity, antimicrobial resistance, and the viable but nonculturable state in human pathogenic Vibrio spp.

The morbidity and mortality associated with Vibrio-mediated waterborne diseases necessitates the development of sensitive detection technologies that are able to elucidate the identity, potential pathogenicity, susceptibility, and viability of contaminating bacteria in a timely manner. For this purpose, we have designed a single multiplex PCR assay to simultaneously amplify 95 diagnostic regions (encompassing species/serogroup-specific, antimicrobial resistance, and known toxin markers) and combined it with a long oligonucleotide microarray to create a platform capable of rapidly detecting and discriminating the major human pathogenic species from the genus Vibrio: V. cholerae, V. parahaemolyticus, V. vulnificus, and V. mimicus. We were able to validate this strategy by testing 100 geographically and temporally distributed isolates and observed an excellent concordance between species- and serotype-level microarray-based identification and traditional typing methods. In addition to accurate identification, the microarray simultaneously provided evidence of antibiotic resistance genes and mobile genetic elements, such as sulfamethoxazole-trimethoprim constins and class I integrons, and common toxin (ctxAB, rtxA, hap, hlyA, tl, tdh, trh, vvhA, vlly, and vmhA) and pathogenicity (tcpA, type III secretion system) genes that are associated with pathogenic Vibrio. The versatility of this method was further underscored by its ability to detect the expression of known toxin and virulence genes from potentially harmful viable but nonculturable organisms. The results suggest that this molecular identification method provides rapid and definitive information that would be of value in epidemiological, environmental, and health risk assessment surveillance.

Anti-Infective Agents↗

PubMed2006

Regulation of Aggregatibacter (Actinobacillus) actinomycetemcomitans leukotoxin secretion by iron.

The gram-negative oral and systemic pathogen Aggregatibacter (Actinobacillus) actinomycetemcomitans produces a leukotoxin (LtxA) that is a member of the RTX (repeats in toxin) family of secreted bacterial toxins. We have recently shown that LtxA has the ability to lyse erythrocytes, which results in a beta-hemolytic phenotype on Columbia blood agar. To determine if LtxA is regulated by iron, we examined beta-hemolysis under iron-rich and iron-limiting conditions. Beta-hemolysis was suppressed in the presence of FeCl3. In contrast, strong beta-hemolysis occurred in the presence of the iron chelator deferoxamine. We found that secretion of LtxA was completely inhibited by free iron, but expression of ltxA was not regulated by iron. Free chromium, cobalt, and magnesium did not affect LtxA secretion. Other LtxA-associated genes were not regulated by iron. Thus, iron appears to play an important role in the regulation of LtxA secretion in A. actinomycetemcomitans in a manner independent of gene regulation.

Aggregatibacter actinomycetemcomitans↗

PubMed1987

Guanine nucleotides induce Ca2+-independent insulin secretion from permeabilized RINm5F cells.

The role of guanine nucleotides in insulin secretion was investigated in electrically permeabilized RINm5F cells. Ca2+ stimulated insulin release (EC50 approximately 2 microM Ca2+). The GTP stable analog, GTP gamma S, elicited insulin secretion at vanishingly low Ca2+ concentrations (less than 10(-11) M), slightly potentiated the response to intermediate Ca2+ levels, but exerted less than additive effects at maximal Ca2+ concentrations. The GDP analog, GDP beta S, inhibited both GTP gamma S- and Ca2+-stimulated secretion. The action of GTP gamma S was not mediated by cAMP, as the latter only enhanced Ca2+-induced secretion. In contrast, 12-O-tetradecanoylphorbol-13-acetate, an activator of protein kinase C, promoted insulin release at nonstimulatory Ca2+ levels as well as potentiating the Ca2+ response. GTP analogs stimulated hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdInsP2), as assessed by inositol phosphate generation. However, this could not fully explain guanine nucleotide-induced secretion because: GTP gamma S-stimulated PtdInsP2 breakdown was totally dependent on Ca2+ and abolished at Ca2+ below 10(-11) M; at these Ca2+ levels, activators of protein kinase C were weak or ineffective secretagogues; the GTP analog Gpp(NH)p was much less effective than GTP gamma S in activating PtdInsP2 hydrolysis, while fully mimicking the effect on Ca2+-independent secretion. Both GTP gamma S-induced PtdInsP2 hydrolysis and insulin release were insensitive to pertussis toxin and cholera toxin. The findings point to a guanine nucleotide-regulated site in the activation of insulin secretion different from the known transmembrane signalling systems.

Animals↗

PubMed2007

Application of ganglioside-sensitized liposomes in a flow injection immunoanalytical system for the determination of cholera toxin.

Cholera, an acute infectious disease associated with water and seafood contamination, is caused by the bacterium Vibrio cholerae, which lives and colonizes in the small intestine and secretes cholera toxin (CT), a causative agent for diarrhea in humans. Based on earlier lateral flow assays, a flow injection liposome immunoanalysis (FILIA) system with excellent sensitivity was developed in this study for the determination of CT at zeptomole levels. Ganglioside (GM1), found to have specific affinity toward CT, was inserted into the phospholipid bilayer during the liposome synthesis. These GM1-sensitized, sulforhodamine B (SRB) dye-entrapping liposomes were used as probes in the FILIA system. Anti-CT antibodies were immobilized in its microcapillary. CT was detected by the formation of a sandwich complex between the immobilized antibody and GM1 liposomes. During the assay, the sample was introduced first into the column, and then liposomes were injected to bind to all CT captured by the antibody in the microcapillary. Subsequently, the SRB dye molecules were released from the bound liposomes via the addition of the detergent octyl glucopyranoside. The released dye molecules were transported to a flow-through fluorescence detector for quantification. The FILIA system was optimized with respect to flow rate, antibody concentration, liposome concentration, and injected sample volume. The calibration curve for CT had a linear range of 10-16 to 10-14 g mL-1. The detection limit of this immunosensor was 6.6 x 10(-17) g mL-1 in 200-microL samples (equivalent to 13 ag or 1.1 zmol).

Antibodies↗

PubMed2004

Euroconference on the Biology of Type IV Secretion Processes: bacterial gates into the outer world.

Type IV secretion systems (T4SSs) mediate both protein and ssDNA secretion from a wide range of bacteria into virtually any cell type or into the milieu. It is this versatility that confers on them the ability to participate in many processes of bacterial life that imply communication with their environment. Type IV secretion systems are involved in horizontal DNA transfer to other bacteria and to plant cells, in DNA uptake from the milieu, in toxin secretion into the milieu, and in the injection of virulence factors into the eukaryotic host cell in a number of mammalian and plant pathogens. Recently, a EuroConference addressed the different aspects of the biology of these transmembrane multiprotein complexes, from the crystal structure of the individual components to the modification that the secreted substrates induce in the recipient cell. Significant progress has been made in the understanding of the molecular architecture and mechanism of secretion. The analysis of protein-protein interactions confirms the role of coupling proteins as substrate recruiters for the transporter. The VirB10 component of the complex has come up as a strong candidate for signal transducer. The wide range of effects on the recipient suggests that many effector proteins are secreted. New effector proteins are being identified for both plant and animal pathogens, as are their targets within the host cells. New T4SS members are being identified that perform novel roles, beyond DNA transfer and virulence, such as establishment of symbiotic processes. Our current knowledge of the Biology of Type IV Secretion Processes increases our ability to exploit them as biotechnological tools or to use them as new targets for inhibitors that could constitute a new generation of antimicrobials in the near future.

Animals↗

PubMed1983

Botulinum neurotoxin type E: studies on mechanism of action and on structure-activity relationships.

Single chain type E botulinum neurotoxin was isolated from culture fluids of Clostridium botulinum (strain Alaska E-43). The neurotoxin, which migrated as a single band in polyacrylamide gel electrophoresis with sodium dodecylsulfate, had a molecular weight of approximately 147,000. Single chain type E neurotoxin that was exposed to trypsin was converted to a dichain molecule. Pretreatment of the single chain molecule with 1,2-cyclohexanedione, a reagent that selectively modifies arginine residues, inhibited trypsin-induced generation of the dichain molecule. In dose-response experiments (10(-13) to 10(-9) M) on the isolated neuromuscular junction (phrenic nerve-hemidiaphragm preparation), the dichain neurotoxin was approximately two orders of magnitude more potent than the single chain neurotoxin. Neither specie of neurotoxin (1 pmol/mouse, in vivo; 1 X 10(-11) M, in vitro) was very effective in blocking autonomic transmission (vagus nerve-atrium preparation). The neuromuscular blocking action of the dichain molecule was divided into a sequence of three steps. There was an initial binding step that was relatively rapid, little influenced by temperature and which left the neurotoxin partially accessible to the neutralizing effects of antitoxin. There was a translocation step that was temperature dependent, antagonized by ammonium chloride and methylamine hydrochloride and which caused the neurotoxin to become inaccessible to the neutralizing effects of antitoxin. Finally, there was an intracellular lytic step, during which the toxin blocked excitation-secretion coupling.

Animals↗

PubMed1989

Inhibition of cholera-toxin-stimulated intestinal secretion by CGS 9343B in rats: a specific calmodulin inhibitor.

In this study, the effect of CGS 9343B on cholera-toxin-stimulated intestinal secretion in rats was determined using in vivo isolated loops. This recently developed compound is a potent and specific inhibitor of calmodulin, but not of protein kinase C. At a luminal dose of 15 mg/kg, CGS 9343B has little effect on basal intestinal absorption but completely inhibited the secretory effects of cholera toxin. The less specific calmodulin inhibitor, trifluoperazine, has a similar antisecretory effect, but unlike with CGS 9343B, severe toxicity was noted at luminal doses of 7.5 mg/kg. In animals where two intestinal loops were created, one with cholera toxin alone and the other with CGS 9343B and cholera toxin, significant inhibition of secretion was observed in both loops, consistent with a systemic effect of this compound. Finally, both CGS 9343B and trifluoperazine inhibited choleratoxin stimulated increases in mucosal cyclic AMP content, whereas basal levels were unaffected. We conclude that CGS 9343B significantly inhibits choleratoxin-stimulated intestinal secretions, possibly by inhibition of calmodulin-dependent adenylate cyclase activity. Its lack of major toxicity at therapeutic doses makes this compound potentially useful for the treatment of enterotoxigenic diarrheal diseases.

Animals↗