Optimized arylomycins are a new class of Gram-negative antibiotics

Abstract

Multidrug-resistant bacteria are spreading at alarming rates, and despite extensive efforts no new class of antibiotic with activity against Gram-negative bacteria has been approved in over fifty years. Natural products and their derivatives have a key role in combating Gram-negative pathogens. Here we report chemical optimization of the arylomycins-a class of natural products with weak activity and limited spectrum-to obtain G0775, a molecule with potent, broad-spectrum activity against Gram-negative bacteria. G0775 inhibits the essential bacterial type I signal peptidase, a new antibiotic target, through an unprecedented molecular mechanism. It circumvents existing antibiotic resistance mechanisms and retains activity against contemporary multidrug-resistant Gram-negative clinical isolates in vitro and in several in vivo infection models. These findings demonstrate that optimized arylomycin analogues such as G0775 could translate into new therapies to address the growing threat of multidrug-resistant Gram-negative infections.

Isotopically Labeled Desthiobiotin Azide (isoDTB) Tags Enable Global Profiling of the Bacterial Cysteinome

“…[4] Especially in the field of antibiotics,covalent inhibitors are prevalent as exemplified by b-lactams, [3] fosfomycin, [5] showdomycin, [6] and optimized arylomycins. [7] Recently,m ethods have emerged to globally identify the exact interaction site of covalent inhibitors in ac ompetitive fashion. [2a,b,8] In this way,many pockets that can bind covalent ligands are identified in parallel using as mall library of covalently reactive molecules.T his technology is especially well established for profiling cysteine residues using methods based on the isoTOP-ABPP (isotopic tandem orthogonal proteolysis activity-based protein profiling) platform (Figure 1a).…”

Identification of polyketide biosynthetic gene clusters that harbor self-resistance target genes

“…There are more challenges for antibiotic discovery for multi-drug resistant Gram-negative pathogens, since they have a double cell wall, which prevents antibiotic molecules from reaching their intracellular targets. Despite extensive efforts, there have been no new classes of antibiotics approved against Gram-negative pathogens in over fifty years 39 . Since our approach is based on the presence of a putative self-resistance gene within the cluster, it suggests that molecules produced by these clusters would target the host organism.…”

Rapid Intrabacterial Hydrolysis for Activating Antibiotics against Gram-negative Bacteria

“…Although the replacement of succinate by cyclohexane-1,2-dicarboxylic acid produces a prodrug (6) with rather low activity (MIC > 200 M), the conjugation of GG to 6 significantly increases the activity of the prodrug (7, MIC = 50 M). Because the ciprofloxacin derivative, with the diglycine conjugated at the carboxylic acid of ciprofloxacin, hardly shows activity against E. coli (Scheme S5 and Figure S7), we made a ciprofloxacin derivative (8), which has 2-hydroxyacetic acid attach to the piperazine end of ciprofloxacin, for conjugating GG to ciprofloxacin. While 9, the succinate derivative of 8, exhibits lower antibacterial activity (MIC = 1.0 M) than that of 8 (MIC = 0.5 M), the conjugation of GG to 9 results in 10 (MIC = 0.5 M), which is as potent as 8 against E. coli.…”

“…4 Thus, there is an urgent need for developing new antimicrobial approaches against MDR bacterial pathogens. Besides investigating novel agents against new targets in bacteria [6][7][8][9] via previously unexplored mechanisms, another strategy is to enhance the efficacy and safety of the existing antibiotics via drug combinations or increasing specificity. For example, Kahne et al demonstrated that the use of novobiocin analogs greatly lower the dose of polymyxins against Gram-negative bacteria via inhibiting DNA gyrase, binding LptB, and disrupting outer membrane.…”