Countering antibiotic tolerance to fight resistance

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The discovery and subsequent widespread availability of antimicrobial agents revolutionized life as we know it; antibiotics ushered in the era of modern-day medicine, which afforded us the ability to treat, prevent and even eliminate some of the world’s then leading causes of death [1,2]. However, this has not been without consequences.

Bacteria are highly adaptive, and regardless of how effective a drug is, some will survive treatment – antibiotic usage increases the prevalence of these resistant pathogens. Antibiotics can even promote the formation of new types of resistance, facilitating the pathogen’s continued evolutionary success [3,4]. There has yet to be a single commercial antibiotic uncompromised by this process [5,6]. The threat of antibiotic resistance has been plastered all over the WHO and CDC home pages and filled headlines of prominent newspapers in an effort to raise awareness. But is ‘antibiotic resistance’ the true culprit? And if not, what is?

Through studying antibiotic resistance, we have learned a great deal about the evolutionary processes behind it: where it comes from, its ecological prowess, and the routes by which it is disseminated. Unfortunately, this has revealed some frightening features of multidrug-resistant pathogens. For example, we’ve learned that resistance genes tend to cluster on mobile genetic elements that can be exchanged via horizontal gene transfer in a matter of minutes [7] – and some of these mobile elements can carry upwards of 14 additional resistance genes [8,9]. We’ve also learned that bacteria communicate amongst each other to coordinate the expression of their costly resistance genes [10–12]. These population-wide strategies have only added an additional layer of complexity to the puzzle of bacterial survival.

Advances in our conceptual understanding of how bacteria evolve resistance have led to the discovery that bacteria can often survive treatment without being resistant at all. Yes, even bacteria that are not genetically ‘resistant’ can display what’s known as antibiotic tolerance [13]: while resistance is characterized by an inheritable increase in a bug’s minimum inhibitory concentration (MIC) of a drug (e.g., a higher antibiotic concentration is needed to inhibit growth), tolerance is a phenotypic state that protects the bug from antibiotic exposure. As a result, the MIC is often as low as in susceptible counterparts’ [14]. Despite appearing sensitive, tolerant infections are regularly observed in the clinic, and can significantly compromise treatment efficacy [14,15]. This underlines the difficulty in separating tolerance from resistance: as long as tolerance exists in a population, it is challenging to know if resistance is truly to blame for ineffective treatments. If a population is merely tolerant, inhibiting or even reversing resistance may not be sufficient.

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