Investigational Antimicrobial Agents of 2013

Abstract

SUMMARY New antimicrobial agents are always needed to counteract the resistant pathogens that continue to be selected by current therapeutic regimens. This review provides a survey of known antimicrobial agents that were currently in clinical development in the fall of 2012 and spring of 2013. Data were collected from published literature primarily from 2010 to 2012, meeting abstracts (2011 to 2012), government websites, and company websites when appropriate. Compared to what was reported in previous surveys, a surprising number of new agents are currently in company pipelines, particularly in phase 3 clinical development. Familiar antibacterial classes of the quinolones, tetracyclines, oxazolidinones, glycopeptides, and cephalosporins are represented by entities with enhanced antimicrobial or pharmacological properties. More importantly, compounds of novel chemical structures targeting bacterial pathways not previously exploited are under development. Some of the most promising compounds include novel β-lactamase inhibitor combinations that target many multidrug-resistant Gram-negative bacteria, a critical medical need. Although new antimicrobial agents will continue to be needed to address increasing antibiotic resistance, there are novel agents in development to tackle at least some of the more worrisome pathogens in the current nosocomial setting.

The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria

“…These considerations likely explain the lack of new antibiotic classes against Gram-negative bacilli for several decades (946,947). New antibiotic pipelines are often available only for Grampositive species and those Gram-negative species lacking significant drug efflux activity and OM barriers (944,948,949), and there is a particular need for drugs against multidrug-resistant A. baumannii and P. aeruginosa.…”

“…Ribosome-targeting omadacyclines (e.g., amadacycline), as new broad-spectrum aminomethylcyclines, possess activity against tetracycline-specific efflux and ribosome protection mechanisms (950,951) but are still rendered inactive by the AcrAB-TolC and MexAB-OprM pumps (944). Similarly, the broad-spectrum agent eravacycline (a new fluorocycline) also lacks activity against A. baumannii, B. cenocepacia, and P. aeruginosa (949,952).…”

“…The broad substrate profile of the major multidrug exporters, the need for the drug to traverse the IM, and the OM permeability barrier clearly indicate key challenges in antibiotic development for Gram-negative bacteria (15,16,(943)(944)(945). The second requirement usually means that the drug must be made somewhat lipophilic, and this makes the drug susceptible to multidrug efflux.…”

Activity of LCB01-0371, a Novel Oxazolidinone, against Mycobacterium abscessus

“…The absorption, distribution, metabolism, excretion, and toxicity (ADMET) test of LCB01-0371 showed high aqueous solubility and good absorption, distribution, metabolism, excretion, toxicity, and pharmacokinetic profiles. In addition, a phase 1 clinical trial of LCB01-0371 was recently completed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy male subjects in a randomized, double-blind, placebo-controlled, single-dose, dose escalation study (31). Therefore, all the efficacies shown in this study are significant in the consideration of a replacement for linezolid in the treatment of M. abscessus infections.…”

New Structural Templates for Clinically Validated and Novel Targets in Antimicrobial Drug Research and Development

“…The threat of multi-drug-resistant pathogens has already been recognized and gained international political attention, leading to several national and international programs and initiatives for the research and development of novel antibiotics (Policy 2010;Boucher et al 2013;Rex 2014;Bush 2015;Eichberg 2015). At this stage, most of the compounds that have recently been launched or that are currently undergoing phase II/III clinical trials are analogs of existing classes (Pucci and Bush 2013;Hesterkamp 2016). As the marketed classes of antibiotics have been extensively reviewed before (Butler et al 2013b;Zetts 2014;Paris 2015), we would like to focus this review on the feasibility to discover novel structural templates with antibiotic activity, and to advance such compounds to late stage pre-clinical as well as clinical development Bou he et al…”