Development of Antibacterial Compounds to Target Drug Resistant Bacteria

Abstract

Nosocomial infections caused by resistant Gram-positive organisms are on the rise, presumably due to a combination of factors including prolonged hospital exposure, increased use of invasive procedures and pervasive antibiotic therapy. Compounding the problem is the emergence of multidrug-resistant (MDR) Gram-positive bacteria [e.g. methicillin resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae and Enterococcus spp.], which render treatment extremely difficult. As a result, last resort antibiotics (e.g. vancomycin, linezolid and daptomycin) are frequently deployed as treatment for these infections, which have the unintended consequence of selecting resistance to these agents. Although antibiotic stewardship and infection control measures are helpful, newer agents against MDR Gram-positive bacteria are urgently needed. Here we describe our efforts that lead to the identification of 5-aminoquinolone 111 with exceptionally potent Gram-positive activity with MICs ≤ 0.06 µg/mL against numerous clinical MRSA isolates. Preliminary mechanism of action and resistance studies demonstrate the 5-aminoquinolones are bacteriostatic but become cidal with 4-8 times MIC, do not select for resistance, and selectively disrupt bacterial membranes over eukaryotic membranes. While the precise molecular mechanism has not been elucidated, the lead compound is non-toxic displaying a therapeutic index of greater than 1000, is devoid of hemolytic activity and has attractive physicochemical properties (clogP = 3.8, MW = 441) that warrant further investigation of this promising antibacterial scaffold for treatment of Gram-positive infections.Another infectious disease that has a massive burden upon the global society and shares the same concern of drug resistance is Tuberculosis (TB). Mycobacterium tuberculosis (Mtb), the causative infectious agent of TB, contains many essential biosynthetic pathways necessary for the survival and virulence of Mtb, but are absent in humans making these pathways prime candidates for antimicrobial compounds. Chorismate biosynthesis is one such essential pathway that has been exploited as a route to TB chemotherapy. Chorismate is also a metabolic hub towards the biosynthesis of a wide array of aromatic small molecules such as folates, mycobactins, aromatic amino acids, and menaquinone in Mtb. Herein, we describe the synthesis of the epimers of 6-fluoroshikimate and methyl-6-fluoroshikimate, known inhibitors of chorismate-utilizing pathways, and biological evaluation of methyl (6S)-6-fluoroshikimate (125) in Mycobacterium. Initial supplementation studies indicate that methyl (6S)-6-fluoroshikimate may act upon unexpected chorismate-utilizing pathways.