By Ceara Harper
It is unquestionable that we are plummeting into a global health catastrophe from the misuse and overuse of antibiotics. With the continued uncontrolled increase of antimicrobial resistance (AMR), we are facing a post-antibiotic era, as current antibiotics become unable to eradicate patients’ microbial infections due to evolving human pathogens. This could see the premature death of a staggering 300 million by 2050 and an eye-watering cost of £64 trillion (or 242.6 Jeff Bezos’) to the global economy (King, 2014).
Considering the scale of the impending AMR iceberg, antibiotic research has been found to be alarmingly underfunded, appropriating less than 1% of UK and European infectious disease R&D funds from 2008-2013 (Bragginton and Piddock, 2014). Additionally, the UK government’s recent funding into antibiotic resistance research has still been meagre: a pitiful £31m committed in 2018 with no indication of a time frame (Department for International Development and Department of Health and Social Care, 2018). For context, if £200m can be amassed to pay for a single footballer (Neymar Jr.), one would hope the prevention of a “post-antibiotic apocalypse” – as described by England’s chief medical officer – would elicit a more serious response from those in power.
In humans, antibiotics are inappropriately and too frequently used to treat a) viral infections b) weak bacterial infections and c) already cured infections. On this latter point, prolonged use of antibiotics increases the risk of developing AMR, while there is no evidence that this is caused by ending an antibiotic course early, despite this message being widely spread (Llewelyn et al., 2017). Whilst clinical misuse of antibiotics leads to an increase in the development of AMR, one should be aware that the vast majority of antibiotics do not go towards treatment of ill and infected human beings. Instead, 73% of global antibiotic supply is pumped into meat production (Kelly, 2019). Use of antibiotics in livestock significantly increases the rise of AMR, with this recently being most pronounced in low- and middle-income countries due to booming meat production and consumption, coupled with inadequate regulation (Kelly, 2019).
An obvious first step in tackling AMR lies in significant reduction and improved regulation of antibiotic use in livestock, globally. Ideally, this could be achieved by reduced meat production and consumption, improvement of animal health and welfare standards and, only where absolutely necessary, use of alternatives to antibiotics. Alternatives for treating disease include bacteriocins, bacteriophage therapy, predatory bacteria and competitive exclusion using a probiotic approach (Allen, 2017). However, currently, antibiotics are heavily used for disease prevention due to the low animal health and welfare standards. For example, in swine, roughly 50% of all antibiotics are used to prevent disease (Apley et al., 2012). For this purpose, vaccines, immunotherapy, prebiotics, probiotics and synbiotics are being researched as alternatives (Allen, 2017). If these alternatives can be used in place of antibiotics in animals, humans and/or industry then selective pressure for the rise and transmission of AMR genes can be reduced (Apley et al., 2012).
Bacteriocins are small peptide toxins produced by bacteria to help drive competition in bacterial systems through their lethality against closely related bacterial strains, although the bacteria themselves have immunity (Lagos, 2013). It has been discovered that there are many bacteriocins that can act very specifically towards clinical bacterial strains, including those with AMR properties. As bacteriocins are peptide based, they can be bioengineered to increase specificity towards their AMR bacterial targets. Depending on the type of probiotic administered to the patient, some strains are able to produce specific bacteriocins to elicit their antimicrobial effect at the site of infection (Cotter et al., 2012). This reduces the collateral damage orally ingested antibiotics have on the host, as their action is more targeted and thus reduces selective pressure for the rise and transmission of AMR genes.
As there are a great variety of bacteriocins produced, varying in size, stability, regulation and mechanism of action, bacteriocins provide a plethora of potential research possibilities for their use as alternatives to antibiotics. Additionally, bacteriocins can have a low oral toxicity with a high potency, adding to their potential as therapeutic agents. With this in mind, Class I bacteriocins (significantly post-translationally modified) are most effective against Gram-positive pathogens. For example, the bacteriocin produced by Streptoccocus Salivarius, a commensal bacterium from the human gut, exhibits potent in vitro activity against Methicillin-resistant Staphylococcus aureus (MRSA), amongst other deadly strains (Cotter et al., 2012 and Mignolet et al., 2018). Class II bacteriocins are unmodified peptides, subdivided into three groups, many of which also possess antimicrobial activity towards Gram-positive pathogens (Drider et al., 2006), such as the food pathogen Listeria monocytogenes (Eijsink et al., 1998). There are a further two classes of bacteriocins: unmodified proteins and complex proteins (Klaenhammer, 1993).
Due to the variety of different bacteriocins, there are many different mechanisms of action, often distinct from those of antibiotics. For Gram-positive bacteria, Class I and II bacteriocins cause pore formation and subsequent cell death by loss of membrane potential, caused by altering mechanisms (Bierbaum and Sahl, 2009). Class I inhibit peptidoglycan synthesis and Class II bind to the pore-forming receptor mannose phosphotransferase system. Class I bacteriocins can also target Gram-positive bacteria through affecting translation. Gram-negative targets of bacteriocins include inhibition of DNA gyrase (to block DNA replication), RNA polymerase (to prevent transcription) and Asp-tRNA synthase (to interfere with mRNA synthesis); all of which lead to bacterial cell death (Parks et al., 2007; Vincent and Morero, 2009).
Many further experiments and clinical trials need to be conducted to determine the in vivo efficacy of bacteriocins, but it is very likely that these toxins will be in extensive use one day. Also, whilst we continue our search for alternatives, we must not turn our backs on the misuse and overuse of antibiotics. Neither should we overlook the possible emergence of bacteriocin-resistance, lest we make the same mistakes again.
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