action of azidothymidine is to bind to the end of the replicating DNA strand (Figure 1A) which blocks DNA strand elongation. Eventually the block can be relieved by the cleavage of azi- dothymidine from the strand (Figure 1B) which allows elongation to resume. The combination is synergistic against colistin-carbapenem resistant CRE. The synergy opens up the development of Low Dose colistin regimen. The combination is faster acting than colistin

alone. It is also active against CRAB and CRPA. Because the two compounds are already in clinical use, the FDA and EMA allow facilitated clinical development paths (such as 505(b)2 by FDA), GMP supply,


binations, all of which are beta-lactamase inhibitors. Clinical trial stage compounds: three are in Phase III, two in Phase II and six in Phase I and information about one is not available. These compounds will be particularly useful in situations where the susceptibility of the pathogen is already known, for example after conventional or rapid diagnostic tests. Where the pathogen is unknown, these new compounds could be useful in combina- tion with other antibiotics if it is suspected that the spectrum needs to be broadened.

established and most

preclinical/toxicity work has been completed, so the development time should be quicker than for NCEs. Importantly, the two compounds are both antibacterial, therefore the enhanced combination of the two should be able to reduce the emergence of resistance. An outline of the pharmacokinetics in 27 healthy volunteers of the combination of azi- dothymidine and colistin is shown in Figure 2. VenatoRX Pharmaceuticals is developing a

boranate-based beta-lactamase inhibitor which is active against serine- and metallo-betalactamases. This is a new class/target. It is combined with cefepime. Spero Therapeutics, Inc has completed a Phase Ib

drug-drug interaction trial of SPR741 which is a novel non-antibacterial polymyxin. It is thought to increase permeability of bacterial membranes, and to enhance the action of beta-lactam antibiotics. In the clinical

trial it was combined with

piperacillin/tazobactam, ceftazidime and aztreonam. AiCuris GmbH. There is limited availability of

information about the structure, activity or partner beta-lactamase inhibitor. GlaxoSmithKline. GSK-3342830 is siderophore-

cephalosporin. The siderophore uses the bacterial iron transport pathway to enhance uptake of the compound through the outer membrane of Gram- negative bacteria. A Phase I trial was suspended in March 2017. Shionogi Inc. Cefiderocol is a siderphore-

cephalosporin. It has completed Phase III clinical trials for hospital-acquired and ventilator-associat- ed pneumonia and critical Gram-negative pathogens.

Further compounds in clinical development which are active against one or two Critical Priority Pathogens There are a further 12 compounds in clinical trials which are in this category. Of these, seven are com-


The case for the development of combinations of antibiotics – rejuvenation with combinations and reduction of resistance emergence Combinations of antibiotics are used to rejuvenate old antibiotics. The classic example is the combi- nation of a beta-lactam and a beta-lactamase inhibitor, such as amoxicillin plus clavulanic acid. Of the 18 compounds in clinical development, with activity against one of more Critical Priority Pathogens, half are combinations with beta-lacta- mase inhibitors. Companies such as Spero and Helperby Therapeutics are developing non-beta- lactamse combinations which rejuvenate old antibiotics against all of the WHO Critical Priority pathogens by permeabilising the bacterial membrane. Another important impact of combinations is to

prevent the emergence of bacterial resistance to antibiotics. In 1948, streptomycin was used to treat tuberculosis patients. Although improvement occurred initially, resistance developed and many died. In 1952, the British Medical Research Council completed a landmark trial in which they treated tuberculosis patients with a combination of strepto- mycin and para-amino-salacylic acid. Resistance did not develop and all the patients survived. This showed that combinations can prevent the

emergence of resistance in patients with tuberculo- sis. This finding has led to the development of the standard four-drug combination regimen which is used to treat tuberculosis today. Unfortunately, if this standard TB regimen has not been used prop- erly, for example, patients fail to follow the course of medication, resistance emerges. The way that combinations prevent the emergence of resistance is thought to be through the mutation frequency of the individual drugs in the combination. For instance, if we consider the combination of old antibiotics A and B which act on different targets, if A has a mutation frequency of 10-6 and B also has a mutation frequency of 10-6, the mutation fre- quency of the combination should be 10-12. In

Drug Discovery World Summer 2018

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