Potential novel antibiotics under review
Despite my dire announcements regarding the potential challenges in treating infectious diseases in the near future, which are coming about due to a combination of biological and economic reasons, there are some reasons to be somewhat optimistic. Via Microbe, the monthly newsletter from the American Society of Microbiology, an article which summarizes some of the research into novel antibiotics that are currently in clinical trials. The article lists at least 39 potential antibacterial compounds under investigation at present, with 25 of those under what is termed Phase 2 or Phase 3. In Phase 2 or Phase 3 trials, the compounds have shown promise in in vitro or animal models, have been found to be safe to administer to humans, and therefore are being assessed to see if they show therapeutic promise in humans. Leading the search for new antimicrobials are small biotech companies such as Cubist here in the US, and the large company Hoffman-La Roche from Switzerland.
One of the very interesting targets is an enzyme called DNA topoisomerase, which catalyzes the unwinding of DNA during the process of DNA replication. Many of these compounds are from the quinolone class of antimicrobials, some of which are easily taken up into host cells, thereby allowing them to be effective against intracellular pathogens such as Legionella pneumophilia and Mycoplasma pneumoniae. The target of these compounds are enzymes that are found in all cells, including human cells, however they are able to demonstrate the principle of selective toxicity by inhibiting the prokaryotic enzymes as opposed to eukaryotic enzymes. Some studies have described side effects where the DNA replication of mitochondria can be inhibited as well.
Other important antimicrobial compounds under investigation inhibit protein synthesis, and a number of compounds are currently under intense review for effectiveness. Some of these compounds have been identified by manipulating known antimicrobials (semi-synthetic compounds) or are the result of new compounds identified by screening environmental microorganisms for inhibitory compounds.
One of the major problems due to antibiotic use in appropriate situations is the rise in other infections, which arise as the normal microbial flora are reduced by the use of the antibiotic. Clostridium difficile infections are increasing in frequency at present, and are themselves beginning to demonstrate antibiotic resistance. Several new compounds under investigation appear to target C. difficile infections very specifically, enabling them to be much more effective against the pathogen in question, while having little effect on other microbes. This approach will help to forestall the emergence of other antibiotic resistance microorganisms, at least for a while.