Addition of ethylamines to the phenols of bithionol and synthetic retinoids does not elicit activity in gram-negative bacteria.

Our labs have demonstrated the activity of bithionol and synthetic retinoids against methicillin-resistant Staphylococcus aureus (MRSA), as well as their membrane-acting mechanism of action. However, the compounds lack activity in gram-negative species. Herein, we apply a known strategy for converting gram-positive agents into broad-spectrum therapies: addition of an alkylamine. By appending an alkylamine to the phenols of these known membrane disruptors, we test whether this approach is applicable to our compounds. Ultimately, biological testing in four MRSA strains and three gram-negative species showed abolished or diminished activity in all our analogs compared to their parent compounds and no gram-negative activity. Thus, we find that alkylamines would not elicit broad-spectrum activity from bithionol or CD437 derivatives.

Phylogeny-Guided Approach Yields Glycopeptides with Unique Action.

Bacteria are extremely adept at overcoming the effects of antibiotics through a variety of mechanisms. As a result, researchers are constantly searching for antibiotics with new mechanisms of action. Culp and coworkers recently utilized a phylogeny-guided approach to mine the genomes of Actinomycetes species for glycopeptides with novel targets. Their efforts yielded the identification of complestatin and corbomycin as antibiotics with a different target than other glycopeptides.

Structure-Activity Relationship and Anticancer Profile of Second-Generation Anti-MRSA Synthetic Retinoids.

We previously reported the antibacterial activity of CD437, a known antitumor compound. It proved to be a potent antimicrobial agent effective against both growing and persister cells of methicillin-resistant Staphylococcus aureus (MRSA). Herein, we report the synthesis of a panel of analogs and their effect on both MRSA and cancer cells. The hydrophobic group of the parent compound was varied in steric bulk, and lipid-mimicking analogs were tested. Biological assessment confirmed that the adamantane moiety is the most effective substitution for antibacterial activity, and some preferential action in cancer over MRSA was achieved.

Signed, Sealed, Delivered: Conjugate and Prodrug Strategies as Targeted Delivery Vectors for Antibiotics.

Innate and developed resistance mechanisms of bacteria to antibiotics are obstacles in the design of novel drugs. However, antibacterial prodrugs and conjugates have shown promise in circumventing resistance and tolerance mechanisms via directed delivery of antibiotics to the site of infection or to specific species or strains of bacteria. The selective targeting and increased permeability and accumulation of these prodrugs not only improves efficacy over unmodified drugs but also reduces off-target effects, toxicity, and development of resistance. Herein, we discuss some of these methods, including sideromycins, antibody-directed prodrugs, cell penetrating peptide conjugates, and codrugs.