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Therapeutics


Figure 1 The mechanism of action of Azidothymidine (AZT): AZT is incorporated into the replicating DNA strand (A) and blocks further replication. In humans, AZT also blocks DNA replication, but is quickly cleaved off the end of the DNA strand (B) and replication is restored


other words, a combination of the two drugs is much less likely to lead to the emergence of resis- tance than one drug which is used on its own. Combinations have also been developed for infec- tions due to Helicobacter pylori and Human Immunodeficiency Virus. These regimens also pre- vent the emergence of resistance. However, combinations have not been well


explored for common Gram-positive and Gram- negative bacterial infections. Here, I describe a small number of examples. While, a combination of trimethoprim and sulfamethoxazole was devel- oped, resistance did develop, probably because the drugs targeted different enzymes in the same metabolic pathway. Combinations of beta-lactam antibiotics and beta-lactamase inhibitors are wide- ly used, but resistance has also arisen to these, pos- sibly because most betalactamase inhibitors are not themselves antibacterial, and so the accompanying beta-lactam antibiotic is, in effect, monotherapy, which quickly leads to resistance. In my view, the way forward is to re-explore the


combination of two or more antibacterial agents, each of which acts on a different mechanism against the target bacterium. In the WHO list of antibiotics which are active against Critical Priority Pathogens, Helperby Therapeutics is developing a Phase II ready combination of azi- dothymidine and colistin. Both of these com- pounds are active against Enterobacteriaceae. Azidothymidine is a bacterial DNA chain replica- tion inhibitor (see Figure 1) and is a new class of antibacterial compound.


Drug Discovery World Summer 2018


The Review on Antimicrobial Resistance (chaired by Jim O’Neill, published in 2016) This review recommended 10 interventions, some- times called the Ten Commandments: 1. A massive global public awareness campaign. There has been some progress in some countries, but much more needs to be done. 2. Improve hygiene and prevent the spread of infec- tion. There is already a wide range in standards between different countries. Although some new efforts are under way, there is a long way to go. For example, the spread of colistin resistance seems to be faster than expected, particularly in bacteria which are also resistant to carbapenems. 3. Reduce the unnecessary use of antimicrobials in agriculture and their dissemination into the envi- ronment. Some good progress in some countries, but still a long way to go. 4. Improve the global surveillance of drug resis- tance in humans and animals. There has been some progress in some countries. 5. Promote new, rapid diagnostics to cut unneces- sary use of antibiotics. Significant progress has been made in the development of new fast diagnos- tic tests for antibiotic resistant bacteria. Some of these tests are already in the market and improved, even faster, tests are in development. The AMR report suggested that rapid diagnostic tests should be a prerequisite for all antibiotic prescribing, but no government is enthusiastic about this idea. But, for new diagnostics to reduce unnecessary antibiot- ic usage and provide effective therapy to those


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