By Rietie Venter, University of South Australia

In the 1940s the well-known British vet James Herriot administered the brand-new antibiotic penicillin to a sick animal and the amazing, speedy recovery that followed was in his words “like witnessing a miracle”. Barely 70 years later, I got an infection in a caesarean wound and I was terrified that these miracle drugs would not work anymore. Luckily for me they still worked and I recovered; many thousands of people are not as fortunate.

How did we go in less than a century from miracle drugs that changed the course of medicine to a situation where about 700,000 people die each year because antibiotics no longer work?

Measuring resistance to antibiotics on an agar plate.

This is the question that is answered in a special issue on antimicrobial resistance published in the journal Essays in Biochemistry.

We all know that antibiotics should not be prescribed unnecessarily, however, the influence of our other activities – such as agriculture and the use of biocides in household items – on the spread of antimicrobial resistance is less well-appreciated. The more antibiotics are used the quicker resistance develops. As we will see, resistance to clinically useful antibiotics develops even when these were not the antibiotics that were used.

Drug efflux pumps confer multidrug resistance

What links a pig in China to antibacterial soaps to the development of resistance against one of our last resort antibiotics? Drug efflux pumps are to blame.  These are proteins that remove antibiotics from bacteria thereby lowering the antibiotic concentration to levels which are too low to have an effect on the pathogen. These proteins do not only transport antibiotics but can pump out many different types of toxic compounds. Hence, the use of any antimicrobials, whether it be growth promoters used in animal feed or antiseptics used in household soaps, can lead to increased production of efflux pumps which will contribute to resistance against our clinically important antibiotics.

Bacterial biofilms also afford organisms a much higher level of antibiotic resistance; bacteria in a biofilm can be up to a 1000x times more resistant to antibiotics than the free swimming form. Biofilms are organised communities of bacteria attached to a surface and encased in a polymer matrix. The plaque on your teeth is an example of a bacterial biofilm. Biofilms in infected wounds, on indwelling devices etc. are responsible for up to 60% of hospital-acquired infections.

Drug efflux pumps are proteins that reside in the bacterial membrane and confer multidrug resistance on an organism by removing a wide variety of toxic compounds from the cell.

Biofilms and persisters allow microorganisms to survive and persist

Bacteria use small chemical molecules to communicate. Translated into English their first signals would say something like: “Is there anyone out there?” Once enough bacteria is present, the signal would change to: “Let’s settle down and form a community.” The microorganisms then alter their gene expression patterns to change from the free swimming form (typical of acute infections) to the highly antimicrobial resistant biofilm form (typical of chronic infections).

Another ingenious way microbes have evolved to persist and survive concentrations of biocides that would kill the normal cells is by entering a dormant state. Most antibiotics work only on actively dividing cells while the small, metabolically inactive dormant cells allow bacteria to evade antimicrobials only to grow again once the antibiotic pressure has been removed.

Bacteria use small chemical molecules to communicate with each other. This can lead to a change in their gene expression and alter their behaviour to change from the free swimming (planktonic) mode to the mode that favours the development of highly drug resistant biofilms.

The antimicrobial drug development pipeline is running dry

According to the WHO, the most critical need for new antibiotics is against a range of Gram-negative organisms that are resistant to some of our last resort antibiotics (e.g. carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa). These organisms are intrinsically very resistant due to the existence of an additional outer membrane that forms a permeability barrier and the presence of an array of drug efflux pumps. No new antibiotics that can act against Gram-negative organisms have been developed in the last few decades.

In spite of the obvious and imminent problem caused by antimicrobial resistance, pharmaceutical companies are not especially keen to develop new antibiotics. As with any other drug candidate, it costs billions of dollars and takes 10-15 years to bring a new antibiotic on the market. However, there is not a large financial incentive as antibiotics are sold cheaply, are taken for a relatively short time (days only) and have a short lifespan of 2-4 years before resistance starts to develop.

While law-makers are grappling with the issue of how to reduce the cost of development or enticements for companies embarking on antimicrobial drug discovery, scientists are thinking of innovative ways to solve the problem of resistance.

Poo protection, crowdsourcing and other ways to combat antimicrobial resistance

One organism that is a huge problem in hospitals and is overtaking MRSA as the number one Gram-positive hospital-acquired pathogen in some countries is Clostridium difficile. A large proportion of people carry C. difficile as part of their intestinal flora; however, the growth of this organism is kept in check by the ‘good’ gut bacteria. When antibiotics are taken for a prolonged time, the more sensitive good bacteria will be killed giving the resistant C. difficile a chance to proliferate in the ecological void that has been created.

The high levels of antimicrobial resistance in C. difficile have made treatment incredibly challenging. Faecal transplant therapy (where the faeces of a healthy donor is used to replenish the good gut bacteria) has now emerged as the most effective therapy to treat recurrent C. difficile diarrhoea.

Another fairly alternative idea is crowdsourcing of antibiotics where an open antimicrobial drug discovery platform is used to test new chemicals from around the world without a charge. In this way, new antimicrobials with novel chemistry or alternative mechanisms of action can be identified and taken into further development.

Other options currently under investigation include developing inhibitors of drug efflux pumps and thereby reversing resistance against antibiotics, or making molecules that interfere with bacterial communication and hence prevent the formation of highly drug-resistant biofilms. Compounds from approved drug libraries could also be repurposed to act as antibiotics per se or to synergise with antibiotics and reverse resistance by, for instance, breaching the permeability barrier of Gram-negative bacteria. Using approved compounds would significantly reduce the cost of drug development making it more feasible for pharmaceutical companies.

Antimicrobial resistance is a global problem that can only be combatted with a broad, coordinated, global approach that takes into account all the factors contributing to resistance. Understanding the mechanisms and spread of antimicrobial resistance and responding in innovative ways, as described in the Essays in Biochemistry themed issue goes some way in addressing the problem.

 

About me

I am Senior Lecturer and Head of Microbiology in the School of Pharmacy and Medical Sciences at the University of South Australia. My research focus is on antimicrobial resistance and I was Guest Editor of the recent Essays in Biochemistry issue on Antimicrobial Resistance.