Antibiotics revolutionised medicine by providing accessible, non-invasive means of combating previously untreatable and often highly contagious infectious diseases. These agents have been in use for more than 70 years and saved countless lives. However, their use was associated with a rapid development of resistant bacterial strains rendering many of antibiotics ineffective. First cases of ineffective therapies were observed soon after the introduction of antibiotics in 1930 – 50s demonstrating the powerful adaptive abilities of microbes. Indeed, each of the major groups of antibiotics has now confronted clinically significant organisms exhibiting resistance, with some microbes presenting multi-drug resistance.
The diminishing arsenal of antibiotics available to clinicians is now a widely recognised global problem. Local guidelines on effective prescribing and patients’ adherence to anti-infective treatments as well as guidelines on the responsible use of antibiotics in animal husbandry and agronomy were publicised to reduce overuse and misuse of antibiotics. In line with these recommendations and warnings, the need for novel anti- microbial agents or more effective delivery strategies is widely expressed. The challenge has now been accepted also within the research domain, as shown for example by the Wellcome Trust 2010 – 2020 strategic plan as well as the recently announced focus of the £10m Longitude 2014 Prize.
The pharmaceutical industry, however, remains relatively unresponsive to the global need for new antimicrobial treatments with only two new classes of antibiotics intro- duced to the market in 30 years before 2010. The generally short-term prescriptions of antibiotics and the tendency to cautiously reserve novel antibiotics active against re- sistant bacteria limit the companies’ appetites to develop new classes of antibiotics. In addition, the regulatory criteria for the approval of antibiotics, for example those related to the non-inferiority trials, have had a significant role in delaying the arrival of new antibiotic products.
There is an inherent challenge in un- derstanding bacterial behaviour. Bacteria display a large degree of behavioural varia- tion and even in genetically identical clon- al populations, investigated under con- trolled environmental conditions, there is variation in gene expression as well as fluctuations in other cellular components. It follows that not only may individual bacteria acquire and express different an- tibiotic-resistance genes, but the level of expression may also vary between the in- dividual bacteria.
Due to this variation, it is necessary to understand bacteria on a single-cell level before we can predict how a bacterial population will respond to antibiotic exposure. Consequently, entirely new methods are required to facilitate the study of bacterial populations on a single-cell level and across generations. This data will provide an understanding of the bacterial dynamic response and adaptation and will enable rational enquiry into resistance-orientated antibiotic development.
Although we know how to be smart about our health, developing innovative medical technologies and thriving pharmaceutical businesses, we have not yet found ways to outsmart bacteria. The nightmare of the medieval plagues scares us more than ever, with our research, business, and regulatory models unable to keep up with the pace of rapidly adapting bacteria. Instead of fighting a losing battle against bacterial evolution, we should perhaps reconsider our efforts. Certainly, developing new methods of single-cell analysis of bacteria is a smart way to start.
About the author:
Michał Włodarski is a PhD candidate in Medical Biophysics at the University of Cambridge. He has previously completed internships at UCL, GlaxoSmithKline R&D and the NHS hospitals. In his current work he combines microscopy methods with microfluidics to study single-cell level bacterial responses to antibiotic treatments. In his free time Michal enjoys hiking, singing and dancing, and sipping chilled piña colada.