Activity of Organoboron Compounds against Biofilm-Forming Pathogens.

Bacteria have evolved and continue to change in response to environmental stressors including antibiotics. Antibiotic resistance and the ability to form biofilms are inextricably linked, requiring the continuous search for alternative compounds to antibiotics that affect biofilm formation. One of the latest drug classes is boron-containing compounds.

Targeting host-specific metabolic pathways-opportunities and challenges for anti-infective therapy.

Microorganisms can takeover critical metabolic pathways in host cells to fuel their replication. This interaction provides an opportunity to target host metabolic pathways, in addition to the pathogen-specific ones, in the development of antimicrobials. Host-directed therapy (HDT) is an emerging strategy of anti-infective therapy, which targets host cell metabolism utilized by facultative and obligate intracellular pathogens for entry, replication, egress or persistence of infected host cells.

Utilization of Existing Human Kinase Inhibitors as Scaffolds in the Development of New Antimicrobials.

The prevalence and continuing expansion of drug resistance, both in clinical and community settings represents a major challenge for current antimicrobial therapy. The different approaches for addressing this challenge include (1) identification of novel antibacterials by repurposing of existing drugs originally that historically target host proteins; and (2) effect target switching through modification of existing antimicrobials. The focus of this manuscript is on these drug discovery strategies, with utility for development of new antimicrobials with different modes of action.

Fragment-Based Lead Discovery Strategies in Antimicrobial Drug Discovery.

Fragment-based lead discovery (FBLD) is a powerful application for developing ligands as modulators of disease targets. This approach strategy involves identification of interactions between low-molecular weight compounds (100-300 Da) and their putative targets, often with low affinity (K ~0.1-1 mM) interactions.

C4-Phenylthio β-lactams: Effect of the chirality of the β-lactam ring on antimicrobial activity.

C4-phenylthio β-lactams are a new family of antibacterial agents that have activity against two phylogenetically distant bacteria - Mycobacterium tuberculosis (Mtb) and Moraxella catarrhalis (M. cat). These compounds are effective against β-lactamase producing Mtb and M.

Addressing Antimicrobial Resistance through New Medicinal and Synthetic Chemistry Strategies.

Over the past century, a multitude of derivatives of structural scaffolds with established antimicrobial potential have been prepared and tested, and a variety of new scaffolds have emerged. The effectiveness of antibiotics, however, is in sharp decline because of the emergence of drug-resistant microorganisms. The prevalence of drug resistance, both in clinical and community settings, is a consequence of bacterial ingenuity in altering pathways and/or cell morphology, making it a persistent threat to human health.

Non-transpeptidase binding arylthioether β-lactams active against Mycobacterium tuberculosis and Moraxella catarrhalis.

The prevalence of drug resistance in both clinical and community settings as a consequence of alterations of biosynthetic pathways, enzymes or cell wall architecture is a persistent threat to human health. We have designed, synthesized, and tested a novel class of non-transpeptidase, β-lactamase resistant monocyclic β-lactams that carry an arylthio group at C4. These thioethers exhibit inhibitory and cidal activity against serine β-lactamase producing Mycobacterium tuberculosis wild type strain (Mtb) and multiple (n=8) β-lactamase producing Moraxella catarrhalis clinical isolates.

Molecular Targets of β-Lactam-Based Antimicrobials: Beyond the Usual Suspects.

The common practice in antibacterial drug development has been to rapidly make an attempt to find ever-more stable and broad-spectrum variants for a particular antibiotic, once a drug resistance for that antibiotic is detected. We are now facing bacterial resistance toward our clinically relevant antibiotics of such a magnitude that the conversation for antimicrobial drug development ought to include effective new antibiotics with alternative mechanisms of action. The electrophilic β-lactam ring is amenable for the inhibition of different enzyme classes by a suitable decoration of the core scaffold.

C4-alkylthiols with activity against Moraxella catarrhalis and Mycobacterium tuberculosis.

Antimicrobial resistance represents a global threat to healthcare. The ability to adequately treat infectious diseases is increasingly under siege due to the emergence of drug-resistant microorganisms. New approaches to drug development are especially needed to target organisms that exhibit broad antibiotic resistance due to expression of β-lactamases which is the most common mechanism by which bacteria become resistant to β-lactam antibiotics.

Antimicrobial properties of organosulfur anti-infectives: a review of patent literature 1999-2005.

The number of organosulfur compounds being patented has been growing. A wide variety of these organosulfur compounds, whether naturally occurring or synthetic, exhibit antibacterial properties. Mechanistically, organosulfur groups can act as metal chelators, powerful nucleophiles or electrophiles depending on the local environment in which a given reaction occurs.

Determination of the cation-chelating potential of C-methylthiolated beta-lactams and their sulfones by electrospray ionization mass spectrometry.

The chelation potential of highly lipophilic C-dimethylthiolated monocyclic beta-lactams was examined using electrospray ionization mass spectrometry (ESI-MS). The metal salts NaCl, KCl, CaCl2, ZnCl2, Cu(NO3)2, CdSO4, MnCl2, and Mg(NO3)2 were used for the analysis. The K+ adducts of the compounds studied were more responsive in ESI analysis, compared to their Na+ adducts, regardless of the oxidation state of the sulfur (in the methylthio or the sulfone groups) and the type of the group adjacent to the lactam carbonyl.

Chemical communication--do we have a quorum?

There are two types of bacterial communication systems, those in which the signal produced by bacteria is directed only at other organisms, and those where the signal is detected by others and self. The latter is involved in adaptation to the environment. The adaptation signals are autoinducers, the response is population density-dependent and has been termed "quorum sensing".

Assessment of the contributions of Na+ channel inhibition and general peripheral action in cocaine-induced conditioned taste aversion.

While the rewarding properties of cocaine appear to be mediated by its blockade of central monoamine uptake, the mechanisms and sites of action for cocaine's aversive effects have yet to be determined. Using the conditioned taste aversion (CTA) preparation, the present study examined the role of Na(+) channel blockade in cocaine's aversive effects by comparing cocaine to the local anesthetic procaine at three doses (18, 32 and 50 mg/kg). Furthermore, the role of cocaine's peripheral actions in its aversive effects was examined by comparing cocaine to the quaternary analog cocaine methiodide (equimolar to the three doses of cocaine) in establishing CTAs.

Lactones: generic inhibitors of enzymes?

The ability to affect eukaryotic and prokaryotic cellular growth, signaling and differentiation is a continuing focus in the pharmaceutical industry. The fundamental ability to affect these cellular processes is inherent in lactones. Lactones, which are ubiquitous in nature, reflect a broad phylogenetic diversity indicative of their ability to act as simple alkylating compounds, with their in situ activities falling into one of two categories, i.

The relationship between inhibitors of eukaryotic and prokaryotic serine proteases.

The ability to inhibit serine proteases is a major focus in the pharmaceutical industry. Serine proteases of medical importance range in phylogenetic diversity from the metallo-proteases, which play a role in pulmonary hypertension, and destruction of the lung parenchyma in emphysema, to those proteases (beta-lactamases), which play a role in the resistance of bacteria to beta-lactam antibiotics. In both the mammalian and microbial systems, the development of serine protease inhibitors has been a focal strategy spurring investigations in the area of serine protease dependent prodrugs that incorporate a bactericidal moiety as well as other classes of metalloprotease inhibitors.

Effect of aryl ring fluorination on the antibacterial properties of C4 aryl-substituted N-methylthio beta-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.

N-thiolated beta-lactams: novel antibacterial agents for methicillin-resistant Staphylococcus aureus.

In this report we describe a new family of N-thiolated beta-lactams that have antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). The compounds show unprecedented structure-activity features and an unusual mode of action for a beta-lactam antibiotic.