This significant characteristic makes possible the relatively rapid elimination of bacteria which otherwise would require treatment for extended periods (6 to 8 months). These have shown to be active against both replicative and hypoxic non-replicating bacilli 1, 2. This search for anti-mycobacterials has identified the very promising bicyclic nitroimidazoles pretomanid (PA-824) and delamanid (OPC-67683), which are currently in clinical phase III with the Global Alliance for TB Drug Development. As a result, the pursuit for new anti-mycobacterials has accelerated in recent years. Tuberculosis (TB) persists as a major global threat, mostly amongst people infected with antibiotic resistant forms of Mycobacterium tuberculosis, the causal agent of the disease 1. This compound showed significant antimicrobial activity (MIC 0.65 mM) against M. These effects were linked to the accumulation of a toxic metabolite methylglyoxal. This targeted the pentose phosphate pathway with significant accumulation seen with fructose-6-phosphate, ribose-5-phosphate and glyceraldehyde-3-phosphate. Metabolites which differed significantly only with pretomanid treatment were identified and mapped on to bacterial metabolic pathways. Pretomanid treatments generated a unique distinctive metabolite profile when compared to ampicillin, ethambutol, ethionamide, isoniazid, kanamycin, linezolid, rifampicin and streptomycin. The identification of key metabolites was independently confirmed by gas-chromatography time-of flight mass spectrometry (GC-tofMS) in comparison to standards. Untargeted high-resolution metabolite profiling was carried out using flow infusion electrospray ion high resolution mass spectrometry (FIE-HRMS) to identify and quantify metabolites. This study aimed to: (i) reveal the metabolome of Mycobacterium smegmatis under pretomanid treatment (ii) compare major sources of metabolite variation in bacteria treated with pretomanid treatment and other antibiotics and (iii) to target metabolites responsible for the killing activity of pretomanid in mycobacteria. Pretomanid is a promising anti-tubercular drug currently at clinical phase III, but its mechanisms of action are currently unclear.
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Rock adds that, even amid the disruption to global business caused by the pandemic, "we have seen some companies outpace their competitors by acting quickly and launching new products and services in a matter of weeks that have typically taken years." This is really a requirement to being successful today.” “They’re finding new sources of value, new sources of revenue, and creating new businesses. “The companies that have stayed at the top for decades are always regenerating,” says Ari. The importance of speed and innovation is something we've also seen in our own work with clients. And in times of uncertainty like COVID-19 the ability for organizations to move fast matters even more.Īri Libarikian, a senior partner and global leader of Leap, McKinsey’s business-building capability, and Rock Khanna, a senior partner and co-leader of our Marketing & Sales Practice in North America, led the discussion with Hoffman and Yeh on blitzscaling, a phrase the two use to describe the set of practices that enable companies to rapidly grow and beat competitors. Being the first to scale is extremely important. They explained that ‘serial business builders’ are organizations that relentlessly come with new ideas and spin them into scalable businesses-businesses that can disrupt entire markets by creating value in radically new ways. In a recent webinar hosted by McKinsey, Reid Hoffman, co-founder of LinkedIn and partner at venture capital firm Greylock, and Chris Yeh, co-founder of the Global Scaling Academy, offered insights. What does that mean, and what do these companies have in common? July 31, 2020Six of the world’s ten largest companies fall into the ‘serial business builder’ category. |
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