From garden to lab: C-3 chemical modifications of tomatidine unveil broad-spectrum ATP synthase inhibitors to combat bacterial resistance.

Antibiotic resistance is escalating alarmingly worldwide. Bacterial resistance mechanisms are surfacing and proliferating across the globe, jeopardizing our capacity to manage prevalent infectious illnesses. Without drastic measures, we risk entering a post-antibiotic era, where even trivial infections and injuries can cause death again.

Small-Colony Variants from Airways of Adult Cystic Fibrosis Patients as Precursors of Adaptive Antibiotic-Resistant Mutations.

Prototypic and their small-colony variants (SCVs) are predominant in cystic fibrosis (CF), but the interdependence of these phenotypes is poorly understood. We characterized isolates from adult CF patients over several years. Of 18 -positive patients (58%), 13 (72%) were positive for SCVs.

Effective Treatment of Intramammary Infection in a Murine Model Using the Bacteriophage Cocktail StaphLyse™.

causes intramammary infections (IMIs), which are refractory to antibiotic treatment and frequently result in chronic mastitis. IMIs are the leading cause of conventional antibiotic use in dairy farms. Phage therapy represents an alternative to antibiotics to help better manage mastitis in cows, reducing the global spread of resistance.

Secondary Staphylococcus aureus intramammary colonization is reduced by non-aureus staphylococci exoproducts.

Non-aureus staphylococci (NAS) and Staphylococcus aureus are pathogens that cause bovine mastitis, a costly disease for dairy farmers, however; many NAS are considered part of the normal udder microbiota. It has been suggested that through a mechanism that remains to be elucidated, NAS intramammary colonization can prevent subsequent infection with other bacterial pathogens. This study shows that in a murine mastitis model, secondary Staph.

Bactericidal Activity of the Bacterial ATP Synthase Inhibitor Tomatidine and the Combination of Tomatidine and Aminoglycoside Against Persistent and Virulent Forms of .

Tomatidine (TO), a steroid alkaloid, exerts a strong bactericidal activity on the infection-persistent phenotype of , the small-colony variant (SCV), with a minimal inhibitory concentration (MIC) of 0.06 μg/ml. Also, the combination of TO to an aminoglycoside (AMG) shows a strong synergistic effect against prototypical (WT) (MIC 0.

The relationship between physicochemical properties, in vitro activity and pharmacokinetic profiles of analogues of diamine-containing efflux pump inhibitors.

Following the optimization of diamine-containing efflux pump inhibitors with respect to in vitro potentiation activity, in vivo stability and acute toxicity, we addressed the question of how to control the pharmacokinetic properties of the series. Upon intravenous administration in the rat, tissue levels of MC-04,124 (the lead compound) were high and prolonged compared to those in the serum. The lipophilicity and basicity of analogues of this compound were systematically varied, and effects on potency and pharmacokinetics explored.

Synthetic dihydropacidamycin antibiotics: a modified spectrum of activity for the pacidamycin class.

Dihydropacidamycins having an antibacterial spectrum modified from that of the natural product pacidamycins and mureidomycins have been synthesized. Synthetic dihydropacidamycins with noteworthy antibacterial activity against wild-type and resistant Escherichia coli have been identified (MIC=4-8 microg/mL). Some dihydropacidamycins are shown to have activity against multi-resistant clinical strains of Mycobacterium tuberculosis.

Conformationally-restricted analogues of efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa.

Conformational restriction of the ornithine residue of the efflux pump inhibitor D-ornithine-D-homophenylalanine-3-aminoquinoline (MC-02,595, 2) furnished bioisosteric proline derivatives that were less toxic in vivo and as active as the lead in potentiating the activity of the fluoroquinolone levofloxacin via the inhibition of efflux pumps in Pseudomonas aeruginosa.

RWJ-54428 (MC-02,479), a new cephalosporin with high affinity for penicillin-binding proteins, including PBP 2a, and stability to staphylococcal beta-lactamases.

RWJ-54428 (MC-02,479) is a new cephalosporin active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The potency of this new cephalosporin against MRSA is related to a high affinity for penicillin-binding protein 2a (PBP 2a), as assessed in a competition assay using biotinylated ampicillin as the reporter molecule. RWJ-54428 had high activity against MRSA strains COL and 67-0 (MIC of 1 micro g/ml) and also showed affinity for PBP 2a, with a 50% inhibitory concentration (IC(50)) of 0.

Peptidomimetics of efflux pump inhibitors potentiate the activity of levofloxacin in Pseudomonas aeruginosa.

Several classes of peptidomimetics of the efflux pump inhibitor D-ornithine-D-homophenylalanine-3-aminoquinoline (MC-02,595) have been prepared and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin in Pseudomonas aeruginosa. A number of the new analogues were as active or more active than the lead, demonstrating that a peptide backbone is not essential for activity.