The Quest for Novel Antimicrobial Compounds: Emerging Trends in Research, Development, and Technologies

Abstract

Pathogenic antibiotic resistant bacteria pose one of the most important health challenges of the 21st century. The overuse and abuse of antibiotics coupled with the natural evolutionary processes of bacteria has led to this crisis. Only incremental advances in antibiotic development have occurred over the last 30 years. Novel classes of molecules, such as engineered antibodies, antibiotic enhancers, siderophore conjugates, engineered phages, photo-switchable antibiotics, and genome editing facilitated by the CRISPR/Cas system, are providing new avenues to facilitate the development of antimicrobial therapies. The informatics revolution is transforming research and development efforts to discover novel antibiotics. The explosion of nanotechnology and micro-engineering is driving the invention of antimicrobial materials, enabling the cultivation of “uncultivable” microbes and creating specific and rapid diagnostic technologies. Finally, a revival in the ecological aspects of microbial disease management, the growth of prebiotics, and integrated management based on the “One Health” model, provide additional avenues to manage this health crisis. These, and future scientific and technological developments, must be coupled and aligned with sound policy and public awareness to address the risks posed by rising antibiotic resistance.

Future Antibacterial Strategies: From Basic Concepts to Clinical Challenges

“…Furthermore, research has been extended to other natural sources such as the oceans (∼1 x 10 6 bacteria per ml of water in the coastal ocean), lakes with ∼2 to 4 x 10 6 bacteria per ml of water in eutrophic lakes (an increase into the rate of supply of organic matter), rivers, sediments, urban soils, or from plants, marine invertebrates, insects and vertebrates [9].…”

“…In environmental bacteria, most antibiotic biosynthetic gene clusters (BGCs) are not expressed under laboratory conditions and are termed 'silent' or 'cryptic'. Thus, naturally-derived drugs were acquired from a minor fraction of constitutively expressed biosynthetic gene clusters, and methods that activate silent BGCs producing novel metabolites would significantly enhance drug discovery [9]. Growth-inhibitory molecules, including antibiotics, can induce the expression of silent BGCs, suggesting that old antibiotics may be used to find new ones [11].…”

“…Devising novel narrow-spectrum therapeutics that only target bacterial pathogens, while minimizing deleterious effects to the human microbiota, is highly desirable [40]. Gut microbiota can be manipulated through active strategies using probiotics, prebiotics, or synbiotics (synergistic combinations of probiotics and prebiotics) [9]. Most probiotics are from lactic acid bacteria, and their effects on the digestive flora depend on the bacterial strain and are determined by bacteriocin production [41].…”

“…Numerous products are in pre-clinical developments but several obstacles (such as proteolytic instability, short in vivo half-life, insolubility, poor bioavailability, and toxicity issues) hamper their translation into therapeutic drugs [9]. Only two AMPs (Lytixar and Pexiganan) are in clinical trials, only for topical use [46].…”

Novel Small-molecule Antibacterials against Gram-positive Pathogens of Staphylococcus and Enterococcus Species

“…The increasing resistances of pathogenic bacteria are one great problem for worldwide health policy, because it means a threat of humanity [1]. Pathogenic bacteria can be found in human surroundings, and drinking water may be contaminated with bacteria in developing countries [2].…”