Image of antibiotic sensitivity test (istock.com/Scharvik)
Antibiotic resistance is one of the biggest public health threats we face today. Speaking at the WIRED Health conference in April, Jim O’Neill, Commercial Secretary to the Treasury in the UK, warned that by 2050, 10 million people a year could die because of resistant infections. In May 2015, the World Health Organization (WHO) launched its global action plan on antimicrobial resistance, which includes the strategic goal “to optimize the use of antimicrobial agents.”
The problem we face is that bacteria and other pathogenic microbes are increasingly resistant to the arsenal of drugs we have available, often making infections untreatable. But while bacteria continue to develop ways of evading our attacks, scientists are developing new weapons.
Recently, researchers working on this have found that some large positively charged compounds, called polycationic dendrimers, can kill bacteria. We wanted to know if it was possible to enhance the antimicrobial effect of their smaller counterparts. Working with a material chemist, Dr. Suk Fun Chin of Universiti Malaysia Sarawak in Malaysia, we prepared a new kind of scaffolding to assemble these molecules together robustly.
The results, which we published in Bioorganic & Medicinal Chemistry Letters, were very exciting: by using carbon nanodots, which are inexpensive, easy to make and non-toxic, we could heighten the antimicrobial properties of small positively charged amines to kill some drug-resistant strains of bacteria.
A new nanomaterial
As their name suggests, carbon nanodots are tiny “dots” or particles of carbon that can be made using simple starch, which means they’re relatively cheap. They’ve been shown to be useful in imaging, sensing, drug delivery and many other areas, and because they’re non-toxic they can also be used in medicine.
Carbon nanodots are covered with chemical groups that can be altered to tether them specifically to other molecules, making them the perfect choice for building tiny scaffolding. We found that these water-soluble carbon nanodots can be surface modified and readily be joined with small polyamines in one step.
Molecules called PAMAM, or poly(amidoamines), come in different sizes, and we wanted to focus on the smaller ones that don’t usually show much antimicrobial activity on their own. By assembling these small PAMAMs on carbon nanodots, we built two molecules: CND-PAM1 and CND-PAM2.
The CND-PAM molecules had the potential to help tackle antibiotic resistance in two ways: killing the bacteria directly and improving the performance of existing antibiotics.
We first tested both versions of CND-PAM against two common bacteria: Escherichia coli and Staphylococcus aureus, both of which can acquire resistance to antibiotics. Our results showed they killed both bacteria, even at low concentrations, but were more effective against E. coli.
To explore this further, we went on to test the CND-PAMs against some three other bacterial species similar to E. coli: Klebsiella pneumonia, Pseudomonas aeruginosa and Acinetobacter baumannii. The US Centers for Disease and Control and Prevention (CDC) categorizes these three bacteria as urgent or serious, as they’re responsible for two-thirds of all healthcare-associated infections.
We tested the CND-PAMs’ antimicrobial action against normal strains and drug-resistant strains of the three bacteria, and found they were effective against them all. In fact, in the case of K. pneumonia, the molecules were four times more effective at killing the drug-resistant than the normal strain.
We then looked at the second possibility: that the molecules could help make existing antibiotics more effective. We tested both the CND-PAMs in combination with two common antibiotics, tetracycline and colistin. Adding CND-PAM1 to tetracycline made it more effective against drug-resistant K. pneumonia, and adding CND-PAM2 to colistin made it four times stronger against A. baumannii.
Nanodots: the future of antimicrobials?
Others have reported previously that some carbon nanotubes have antimicrobial properties, but this is the first time anyone has investigated carbon nanodots in this way. Our results are very exciting – we’ve shown that this new nanomaterial could be used to boost the effectiveness of antibiotics. This makes them a compelling alternative to carbon nanotubes, because they are readily prepared from inexpensive precursors and are water-soluble.
We hope our research will lead to more effective antibiotics, and also that it will inspire other researchers to use carbon nanodots as molecular scaffoldings for a variety of applications.
This international collaboration was made possible through funding from an AAAS Women in International Research Collaboration grant and subsequently a National Science Foundation (NSF) Historically Black Colleges and Universities (NSF HBCU) Undergraduate Program grant.
Read the study
Elsevier has made this article freely available until November 23, 2016:
Maria Ngu-Schwemlein et al: “Carbon nanodots as molecular scaffolds for development of antimicrobial agents,” Bioorganic & Medicinal Chemistry Letters (April 2015)
Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience. This journal is published by Elsevier.