Sonja Dickey

N-Thiolated Bicyclic and Monocyclic β-Lactams

Abstract In this study, we describe the synthesis and features of β-lactam ring systems having an alkylthio substituent on the lactam nitrogen center. The sulfur group acts to enhance the electrophilic character of the lactam carbonyl through electron withdrawal, and in bicyclic systems, reduces pyramidalization of the nitrogen center. Despite their electrophilic nature, these ring systems are chemically stable towards hydrolysis in aqueous media, but can be cleaved at the N–S bond by reducing agents such as triphenylphosphine. N-Methylthio substituted lactams favor a conformation having the sulfur–carbon bond of the SMe group aligned orthogonally with respect to the ring, with a facile interconversion between the cis and trans rotamers. These N-methylthio substituted lactams show potent antimicrobial behavior towards Staphylococcus aureus, including drug-resistant forms, and are not hydrolyzed by β-lactamases. From the data presented, there is a strong suggestion that these lactams may operate through a chemical and biological mechanism of action that is different from all previous classes of β-lactam drugs.

Studies on the antifungal properties of N-thiolated β-lactams

N-thiolated beta-lactams had previously been shown to have antibacterial activity against a narrow selection of pathogenic bacteria including Staphylococcus aureus and Bacillus anthracis, as well as apoptotic-inducing activity in a variety of human cancer cell lines. We now have found that these lactams also possess antifungal activity against Candida and other fungi by exerting powerful cytostatic effects that disrupt the structural integrity of cytoplasmic membranes. The mode of action and structure-activity trends of these lactams as antifungals parallel that previously seen in our antibacterial studies.

Unsymmetric aryl–alkyl disulfide growth inhibitors of methicillin-resistant Staphylococcus aureus and Bacillus anthracis

This study describes the antibacterial properties of synthetically produced mixed aryl-alkyl disulfide compounds as a means to control the growth of Staphylococcus aureus and Bacillus anthracis. Some of these compounds exerted strong in vitro bioactivity. Our results indicate that among the 12 different aryl substituents examined, nitrophenyl derivatives provide the strongest antibiotic activities. This may be the result of electronic activation of the arylthio moiety as a leaving group for nucleophilic attack on the disulfide bond. Small alkyl residues on the other sulfur provide the best activity as well, which for different bacteria appears to be somewhat dependent on the nature of the alkyl moiety. The mechanism of action of these lipophilic disulfides is likely similar to that of previously reported N-thiolated beta-lactams, which have been shown to produce alkyl-CoA disulfides through a thiol-disulfide exchange within the cytoplasm, ultimately inhibiting type II fatty acid synthesis. However, the mixed alkyl-CoA disulfides themselves show no antibacterial activity, presumably due to the inability of the highly polar compounds to cross the bacterial cell membrane. These structurally simple disulfides have been found to inhibit beta-ketoacyl-acyl carrier protein synthase III, or FabH, a key enzyme in type II fatty acid biosynthesis, and thus may serve as new leads to the development of effective antibacterials for MRSA and anthrax infections.

N-Thiolated β-Lactam Antibacterials: Defining the Role of Unsaturation in the C4 Side Chain

N-Methylthio beta-lactams represent a novel family of antibacterial agents for methicillin-resistant Staphylococcus aureus (MRSA). The structure-activity functions and mechanism of action of these compounds, although still largely undefined, differ dramatically from those of all previously reported beta-lactam antibiotics. Prior work has established that the N-alkylthio moiety is required for antibacterial activity, and that a variety of unsaturated groups can be tolerated at C(4) of the lactam ring. This report describes the effect that unsaturation within the C(4) substituent has on antibacterial activity of these interesting new N-thiolated beta-lactams.

Effect of aryl ring fluorination on the antibacterial properties of C4 aryl-substituted n-methylthio β-lactams

4-Aryl-substituted N-thiolated beta-lactams are a new family of antibacterial agents possessing unique structure-activity profiles and a mode of action. Unlike traditional beta-lactam antibiotics, which require highly polar enzyme-binding groups, these lactams bear hydrophobic groups on their side chains. In this study, we examine the effect that increasing hydrophobicity, through fluorine substitution in the C(4) aryl ring, has on the antibacterial properties.

DIETARY FATTY ACID (FA) EFFECTS UPON GROUP B STREPTOCOCCAL (GBS) INFECTION. † 1893

Dietary FA effects upon the immune response may be mediated in part by effects upon proinflammatory cytokines and eicosanoids. The impact of maternal diet FA composition upon mortality from GAS infection was studied in neonatal rat pups. Methods: Timed pregnant dams were fed, beginning on day 2 of gest. and throughout lactation, either chow (control) or a purified diet whose fat source (22% of cals) was either corn oil (high n6) or menhaden fish oil (high n3). On day 3 of life, pups were culled to 10 pups per dam and were randomly cross-fostered among dams fed the same diets to minimize litter effects. Milk was removed from culled pup stomachs for FA analysis. Exp 1: On day 7 of life, pups were injected i.p. with 0.1 ml of a suspension of GAS Type I as follows: one litter per diet with 106.5 organisms, and one litter per diet with 107.5 organisms. Data from both doses were combined for statistical analyses. Exp 2: On day 7 of life, pups (n=1 litter per diet group) were injected with 107 GAS organisms and sacrificed 48 hours later. Blood was collected for GAS culture and analysis of serum TNFα levels; spleen weights were determined. Results: FA composition of milk reflected maternal diet (Table). Exp 1: 100% of pups in the chow and corn oil groups died within 96 hours, while 33% survived in the fish oil group (p=0.002 fishers exact (permutation) test). Exp 2: Spleen weights (as% body weight) were significantly higher in the fish vs corn and chow groups. Preliminary cytokine data suggest lower serum levels of TNFα and a trend towards fewer positive blood culture in pups of the fish group. Conclusion: The FA composition pre- and/or postnatal diet may affect immune response to bacterial sepsis. Funded in part by Ross Laboratories.