The Evolving Role of Chemical Synthesis in Antibacterial Drug Discovery

Abstract

The discovery and implementation of antibiotics in the early twentieth century transformed human health and wellbeing. Chemical synthesis enabled the development of the first antibacterial substances, organoarsenicals and sulfa drugs, but these were soon outshone by a host of more powerful and vastly more complex antibiotics from nature: penicillin, streptomycin, tetracycline, and erythromycin, among others. These primary defences are now significantly less effective as an unavoidable consequence of rapid evolution of resistance within pathogenic bacteria, made worse by widespread misuse of antibiotics. For decades medicinal chemists replenished the arsenal of antibiotics by semisynthetic and to a lesser degree fully synthetic routes, but economic factors have led to a subsidence of this effort, which places society on the precipice of a disaster. We believe that the strategic application of modern chemical synthesis to antibacterial drug discovery must play a critical role if a crisis of global proportions is to be averted.

Tetrabromobisphenol A (TBBPA) exhibits specific antimicrobial activity against Gram-positive bacteria without detectable resistance

“…1 Continuous efforts have been made to battle antibacterial resistance through exploring the potential options of using natural products and synthetic compounds of antimicrobial activity. 2 Tetrabromobisphenol A (TBBPA) is a synthetic, highly lipophilic halogenated aromatic molecule, and has been widely used as a brominated flame retardant to reduce the risk of ignition and to prevent firerelated damage.…”

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“…Succinctly, they are one of important class of compounds having therapeutic potential for the treatment of various diseases 24 . Schiff bases which can bind or cleave DNA are now in great consideration due to their importance in the development of anticancer and antimicrobial agents 1,4,5,6 . Schiff bases are characterized by imine group -N=CH-and they explicate the mechanism of transamination and racemization reactions in biological system 7 .…”

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

“…Table 1: Bacterial targets and approved antimicrobial compounds addressing them. (Brötz-Oesterhelt and Brunner 2008;Kohanski et al 2010;Lewis 2013;Butler et al 2013b;Wright et al 2014;Bush 2015) (Mullane and Gorbach 2011;Scott 2013;Butler et al 2013b;Zhanel et al 2015Zhanel et al ) (1948 Lipid II and lipid III -The bottlenecks in peptidoglycan and wall teichoic acid synthesis Known, clinically validated targets represent the most promising choice for the development of novel antibiotics, in particular when novel chemical scaffolds that address different binding sites compared to existing drugs break resistance. An excellent example for such a target is lipid II 6 (Scheme 2) (Breukink and de Kruijff 2006;de Kruijff et al 2008), an amphiphilic, membrane-anchored peptidoglycan precursor molecule that is essential for cell membrane functionality.…”

“…It has to be clearly stated that most of such analogs (socalled step-innovations ) confer a medical benefit (Wright et al 2014), e.g. through enlarged safety windows, improved ADMET properties, circumvented bacterial efflux or degradation systems (Brötz-Oesterhelt and Brunner 2008) and sometimes impressive shifts in antibacterial activity from a distinct activity against Gram-positive or Gram-negative bacteria to a broad spectrum antibiotic activity, as demonstrated by the 4 th and 5 th generation of cephalosporins, advanced tetracycline or fluoroquinolone analogs (Wright et al 2014). However, the evolution of bacterial resistance against these analogs is often faster due to cross resistances (Coates et al 2011).…”