Current Medicinal Chemistry - Volume 8, Issue 14, 2001

The emergence of active efflux as a major causative factor in antibiotic resistance has been one of the most significant trends in antiinfective chemotherapy over the last decade. The phenomenon affects virtually all classes of antibiotics and frequently results in multi-drug resistant phenotypes. This review analyzes efflux pumps of clinical significance and examines their impact on different antibiotic classes relative to other mechanisms of resistance. Progress in strategies to combat efflux-mediated resistance by modification of existing antibiotics or identification of efflux pump inhibitors is also reviewed.

Complete DNA sequence information has now been obtained for several prokaryotic genomes, defining the entire genetic complement of these organisms. The collection of genomic data has provided new insights into the molecular architecture of bacterial cells, revealing the basic genetic and metabolic structures that support viability of the organisms. Genomic information has also revealed new avenues for inhibition of bacterial growth and viability, expanding the number of possible drug targets for antibiotic discovery. This review examines how genomic sciences and experimental tools are applied to antibacterial target discovery, the necessary first step in the development of new antibiotic classes. Significant advances have been realized in the development of functional genomic, comparative genomic, and proteomic methods for the analysis of completed genomes. The combination of these methods can be used to systematically parse the genome and identify targets worthy of inhibitor screens. Two basic categories of targets emerge from this exercise, comprising in vitro essential targets required for bacterial viability on synthetic media and in vivo essential targets required to establish and maintain infection within a host organism. Current use of genomic information is focused primarily on a definition of all in vitro essential targets that satisfy criteria of selectivity, spectrum, and novelty. As the genomes of additional bacterial pathogens are solved, it will be possible to select in vivo essential targets common to groups of select pathogens (e.g., bacterial agents of community acquired pneumonia) or even pathogen-specific targets. Consideration of host-pathogen interactions, defined at the level of gene expression for each organism, might provide novel therapeutic options in the future.

Recent semi-synthetic studies of erythromycin A culminated in the discovery of two ketolide drug candidates, HMR-3647 and ABT-773, for the treatment of community-acquired bacterial infections caused by both macrolide- and β-lactam-susceptible and -resistant S. pneumoniae, gram negative bacteria, and intracellular atypical pathogens. The discovery of ketolides has rekindled interest in macrolides, and recent efforts have also led to a novel class of 4”-carbamates with activity against macrolide-resistant organisms. This review is an account of recent developments on ketolides and macrolides in terms of both chemistry and antibacterial activity.

Resistance to glycopeptides in enterococci, which first emerged in the late 1980's and is now widespread mainly in the United States, is posing a serious clinical problem due to the lack of alternative and efficacious therapeutic options, particularly against infections caused by VanA strains that are highly resistant to glycopeptides and almost all other antibiotics. In addition, isolates of Staphylococcus aureus, known as GISA, that are poorly susceptible to vancomycin and teicoplanin have been identified. Thus, there is an urgent need to develop new and more potent glycopeptides that are active against these problematic organisms.The following review will focus on the development of second-generation glycopeptides, namely LY333328 (Eli Lilly) and BI 397 (Biosearch Italia, in license to Versicor for North America), which are currently undergoing clinical trials in humans for their promising activity against VanA enterococci (LY333328), staphylococci (BI 397), and penicillin-resistant pneumococci. Both compounds were identified as the result of chemical programs that were aimed at pursuing activity of vancomycin-like or teicoplanin-like natural glycopeptides against VanA enterococci and multidrug-resistant staphylococci.More recent approaches toward glycopeptides modified in their heptapeptide core are also described. These include compounds in which amino acids 1 and 3 are replaced with other amino acid moieties such as in the modification of the asparagine side chain on residue 3 as well as attempts to change the structure of the heptapeptide backbone in positions that are critical for the molecular interaction with susceptible D-Ala-D-Ala and resistant D-Ala-D-Lactate targets.Covalently linked glycopeptide dimers and vancomycin derivatives in which vancosamine is suitably replaced with other sugar moieties will also be covered.

The development of antibacterials was a very successful endeavor in the pharmaceutical company repertoire through the late 1970s, when interest in investing in antibiotic research and development temporarily waned. More recently, there have been a number of failures in late stage development or post-launch of human antibiotics. The answer to the dilemma of less-than-desired success may be the introduction of novel classes of agents, as well as development of new agents in traditional classes. This review provides an overview of the various “miscellaneous” antibacterials in development, excluding glycopeptides, macrolides, ketolides, and oxazolidinones. Among the agents highlighted in this review are the clinical candidates of quinolones, everninomycins, carbapenems, lipopeptides, glycylcyclines, and cephems. In several cases, certain quinolone agents described in this review will have been approved for marketing before press time.