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.

Evaluation of the Mitragynine Content, Levels of Toxic Metals and the Presence of Microbes in Kratom Products Purchased in the Western Suburbs of Chicago.

Kratom (, Korth) is a tree-like plant that is indigenous to Southeast Asia. Kratom leaf products have been used in traditional folk medicine for their unique combination of stimulant and opioid-like effects. Kratom is being increasingly used in the West for its reputed benefits in the treatment of pain, depression and opioid use disorder.

Comparison of In Vitro Chlamydia muridarum Infection Under Aerobic and Anaerobic Conditions.

Although Chlamydia infects host body regions that are hypoxic to anoxic, standard Chlamydiae culture conditions are in CO enriched (5%) atmospheric oxygen (21%). Because of its success in causing disease in principally anaerobic body sites, e.g.

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.

Anaerobic Growth and Maintenance of Mammalian Cell Lines.

Most mucosal surfaces along with the midpoints in tumors and stem cell niches are geographic areas of the body that are anoxic. Previous studies show that the incubation in normoxic (5% CO2 in air) or hypoxic (low oxygen levels) conditions followed by an anoxic incubation (an absence of free oxygen) results in limited viability (2-3 days). A novel methodology was developed that enables an anoxic cell cultivation (for at least 17 days; the maximum time tested).

Prevalence of a Cefazolin Inoculum Effect Associated with Gene Types among Methicillin-Susceptible Staphylococcus aureus Isolates from Four Major Medical Centers in Chicago.

The efficacy of cefazolin with high-inoculum methicillin-susceptible (MSSA) infections remains in question due to therapeutic failure inferred as being due to an inoculum effect (InE). This study investigated the local prevalence of a cefazolin InE (CInE) and its association with staphylococcal gene types among MSSA isolates in the Chicago area. Four medical centers in Chicago, IL, contributed MSSA isolates.

A method for the long-term cultivation of mammalian cells in the absence of oxygen: Characterization of cell replication, hypoxia-inducible factor expression and reactive oxygen species production.

The center of tumors, stem cell niches and mucosal surfaces all represent areas of the body that are reported to be anoxic. However, long-term study of anoxic cell physiology is hindered by the lack of a sustainable method permitting cell cultivation in the complete absence of oxygen. A novel methodology was developed that enabled anoxic cell cultivation (17d maximum time tested) and cell passage.

Attenuation of antimicrobial activity by the human steroid hormones.

Upon entering the human host, Staphylococcus aureus is exposed to endogenous steroid hormones. The interaction between S. aureus and dehydroepiandosterone (DHEA) results in an increased resistance to the host cationic defense peptide, β-1 defensin, as well as vancomycin and other antibiotics that have a positive charge.

Host environmental signals and effects on biofilm formation.

Biofilm matrix formation is a phenotype linked to the ability to survive a hostile host environment that includes the presence of antimicrobial peptides and serum factors. Multiple hormones and other host derived factors have been shown to function as exogenous quorum signaling compound homologs that inform microbes of their in situ presence, thus triggering a shift from a planktonic to the sessile biofilm phenotype. The focus of this review is to describe the impact various host-derived factors have on the initial steps required for biofilm formation, i.

Determination of Biofilm Initiation on Virus-infected Cells by Bacteria and Fungi.

The study of polymicrobial interactions across the taxonomic kingdoms that include fungi, bacteria and virus have not been previously examined with respect to how viral members of the microbiome affect subsequent microbe interactions with these virus-infected host cells. The co-habitation of virus with bacteria and fungi is principally present on the mucosal surfaces of the oral cavity and genital tract. Mucosal cells, particularly those with persistent chronic or persistent latent viral infections, could have a significant impact on members of the microbiome through virus alteration in number and type of receptors expressed.

Herpes Simplex Virus (HSV) Modulation of Staphylococcus aureus and Candida albicans Initiation of HeLa 299 Cell-Associated Biofilm.

Although herpes simplex virus type-1 (HSV-1), and type-2 (HSV-2), Staphylococcus aureus and Candida albicans co-habit the oral and genital mucosa, their interaction is poorly understood. We determined the effect HSV has on bacterial and/or fungal adherence, the initial step in biofilm formation. HeLa229 cells were infected with HSV-1 (KOS) gL86 or HSV-2 (KOS) 333gJ (-) at a multiplicity of infection (MOI) of 50 and 10.

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.

Antimicrobial and biofilm effects of herbs used in traditional Chinese medicine.

Of the twenty-two components of tea decoctions commonly used to treat infections, only Scutellaria, Taraxacum, Tussilago and Glycyrrhiza exhibited antimicrobial activity. The activity, when present, was organism specific, i.e.

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.

Possible role of sarA in dehydroepiandrosterone-mediated increase in Staphylococcus aureus resistance to vancomycin.

Background: Dehydroepiandrosterone (DHEA), a steroid present throughout life, can induce an increase in resistance to vancomycin in methicillin-sensitive and methicillin-resistant clinical isolates of Staphylococcus aureus.

Methods: The in vitro effect of DHEA on vancomycin killing of S. aureus with mutations in sarA and/or agr was determined by standard microtiter protocols and time to kill determinations.

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".

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.