In September of 2016, the UN General Assembly declared that the issue of antimicrobial resistance (AMR) presented a fundamental threat towards human health, development, and security. In response to this declaration, officials from member nations committed themselves to taking a coordinated and expanded approach towards addressing the root causes of AMR. This marked only the fourth time that the UN General Assembly had taken up a health issue (Ebola, HIV, and noncommunicable diseases being the other three times)1. Six months later, it is now time to retrogressively analyze some of the progress that the global community has made towards tackling what is currently classified as the most prevalent health threat facing the planet.
As part of the blueprint that was put forward to reduce the impact of AMR on global health by 2018, member countries agreed to put specific systems in place to ensure citizen access to clean water and sanitized living conditions. In addition, the UN renewed its commitment to educating doctors and patients about the appropriate use of antibiotics and immunizations. However, the plan also highlighted the failures that are often associated with bringing new drugs to the market and called for new incentives for investments made in developing new and affordable drugs that can replace those that have lost their effectiveness over time. Fortunately, the increase in support and urgency has led to several potential long term solutions which may curb the threat of AMR.
When it comes to countering antimicrobial resistance on a medicinal level, there are two basic approaches that scientists can choose to take. The first of these approaches involves the research and development of new treatments to replace the old ones that have become ineffective at fighting off pathogens. This includes taking existing, but underused antibiotics and repurposing them to succeed treatments that have become over-prescribed and over-utilized. The discovery of these new treatments is crucial in the continued fight against AMR, because it is important to avoid running out of viable options to treat a certain disease. Unfortunately, the rate at which promising antimicrobial agents continue to be developed is inconsistent at best, as the effectiveness of most new drugs remains uncertain until they can be approved by the FDA and other global drug administrations. As a result, most new drugs fail to reach the market in a timely manner, which makes finding new options that can be implemented immediately even more challenging.
One promising option in the treatment of gram-positive bacteria is Linezolid, an antimicrobial agent that acts by inhibiting protein synthesis in vancomycin-resistant enterococci (VRE) and methicillin-resistant staphylococci. Linezolid has been approved by the FDA and has been available since the early 2000s. However, it has been largely ignored in favor of Vancomycin and Teicoplanin, both of which are commonly used to treat gram-positive bacterial infections such as pneumonia, meningitis, and food poisoning. Unfortunately, the emergence of resistance to glycopeptides in gram-positives has reduced the effectiveness of both of these antibiotics.
Unlike Vancomycin and Teicoplanin, Linezolid resistance among gram-positive pathogens remains at less than 1%, making it an appealing alternative. Linezolid has also exhibited other notable advantages, such as lack of rapid in-vitro resistance and the absence of inherent cross-resistance to other classes of antimicrobial bacteria. In addition, the mechanism by which Linezolid acts is unique in and of itself, because it appears to inhibit the formation of the initiation complex during protein synthesis. This unique mechanism plays a large role in the absence of cross-resistance in Linezolid and is part of the reason why it is such an appealing alternative to glycopeptide antibiotics.2
The second basic approach towards countering antimicrobial resistance on a medicinal level involves reversing bacterial resistance towards existing treatments that are already ineffective or in danger of becoming so. This is inherently the more challenging of the two approaches, but also has the potential to be more effective. Therefore, while developing and repurposing new treatments serves as a Band-Aid for a continuously growing problem, the reversal of antibiotic resistance in existing medications can be seen as the key towards solving what has become a global health crisis.
Until recently, most of the progress made in directly reversing AMR has been minimal. However, the recent spike in urgency led by the UN Global Health Report has led to an increase in funding, support, and activity in this subfield. The most recent breakthrough was led by a team of US researchers that successfully constructed a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO), which was able to inhibit the expression of the antibiotic resistance gene NDM-1, resulting in the restoration of antibiotic susceptibility in all bacteria carrying this gene. NDM-1 associated resistance has spread at a rapid rate in gram-negative bacterial species, such as Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii, and has led to bacterial resistance to the carbapenems, which include some of the most powerful and widely used antibiotics such as Imipenem, Meropenem, Etrapenem.
PPMOs such as the one constructed by these researchers are synthetic nucleotides that are believed to prevent translation of a specific gene by selectively binding the mRNA. This has some of its own unique advantages, as just one of these synthesized PPMOs can target multiple species of bacteria that contain the NDM-1 gene3. However, an issue that the study did not address is whether or not bacterial species will end up developing a resistance towards the PPMOs that inhibit the resistance gene itself. While the effects of these potential complications remain to be seen, this still remains a notable breakthrough as it marks the first time that a gene-specific therapeutic targeted towards the NDM-1 resistance gene has been demonstrated to work in-vivo.
As was the case with the Ebola crisis, the United Nation’s plan to tackle AMR has brought increased attention in the form of funding, education, and research. While the effectiveness of this plan remains unclear after only six months, the strides that the global research community has taken during this short time appear to be promising. So in the end, while natural selection remains a powerful force, there is still hope that we can slow or reverse the effects of antimicrobial resistance through proper education, research, and an unwavering commitment towards solving this crisis.
- High-Level Meeting on Antimicrobial Resistance – General Assembly of the United Nations. http://www.un.org/pga/71/2016/09/21/press-release-hl-meeting-on-antimicrobial-resistance/.
- Bialvaei, A. Z., Rahbar, M., Yousefi, M., Asgharzadeh, M. & Kafil, H. S. Linezolid: a promising option in the treatment of Gram-positives. Journal of Antimicrobial Chemotherapy 72, 354–364 (2016).
- Sully, E. K. et al. Peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) restores carbapenem susceptibility to NDM-1-positive pathogens in vitro and in vivo. Journal of Antimicrobial Chemotherapy (2016). doi:10.1093/jac/dkw476