Antimicrobial resistance is a rapidly growing issue worldwide, with resistance to some degree being present in every country. Bacteria showing resistance to last-resort antibiotic treatments such as carbapenems and colistin are becoming more abundant as time passes, limiting the treatment options for those suffering from diseases with a root bacterial cause. This problem will only become a larger burden upon society as treatment options narrow in scope and consequences of infection become much worse. Synthetic biology – a rapidly growing field using the ideologies of engineering to design and assemble components from living organisms – may hold a solution to this growing antimicrobial resistance crisis. Researchers worldwide are utilising the tools and thought processes behind synthetic biology to engineer novel antibiotics which target multi-drug resistant bacteria in new ways, providing new treatment options for those suffering from previously treatable conditions. This review will discuss recent advances in the use of synthetic biology methodologies for the production of novel antimicrobials.
BGC – biosynthetic gene cluster
MRSA – methicillin-resistant Staphylococcus aureus
An antibiotic can be defined as any substance which inhibits bacterial growth or causes bacterial cell death. Antibiotics have been utilised by us for decades in order to treat diseases with a bacterial cause, such as infectious diseases like tuberculosis, pneumonia, or bacterial meningitis. Pre-operative antibiotics have also reduced the death count from surgeries due to the decrease in post-surgical infection (Conte and Barriere, 2002).
Antibiotics were classically discovered from the growth of soil-dwelling bacteria, though others originate from various plant and fungal species (Demain, 2009). Actinomycetes – an order of Actinobacteria – are astonishingly prolific in the number of antibiotics they can produce – approximately 45% of antibiotics of microbial origin (~22,500) are produced by actinomycetes (Bérdy, 2005), and approximately 75% of those are made by bacteria in the Streptomyces genus (Demain, 2014). One of the most prolific producers in the Streptomyces genus is Streptomyces hygroscopicus, which is capable of producing nearly 200 different antibiotics (Demain, 2014). In nature, various other microbial species utilise antibiotics in their arsenal of defence against bacteria – antibiotics have been found in many other organisms including strains of Bacillus subtilis (Demain, 2014).
Figure 1: Timeline of antibiotic discovery. Highlighting the ‘Golden Age’ of antibiotic discovery as a consequence of Selman Waksman’s work (Waksman and Woodruff, 1940) in contrast to the dearth of new antibiotics discovered in the last two decades. Dates described in (Silver, 2011) and (Ling et al., 2015).
The earliest natural product antibiotic was penicillin, famously discovered in 1928 by Alexander Fleming from the growth of the fungi Penicillium nonatum. Following the discovery and characterisation of penicillin, and establishment of a systematic screening method by Selman Waksman in the 1940s (Waksman and Woodruff, 1940), a golden age of antibiotic discovery occurred in the decades directly following. Since then there have been several classes of antibiotics established, each with different modes of action. Many antibiotics act through stalling of the bacterial ribosome (i.e. erythromycin), whilst others inhibit key bacterial enzymes (i.e. ?-lactam antibiotics such as penicillin). Antibiotics also vary in size, from small molecules to long polypeptide chains (Demain, 2014). The last major class of antibiotics (lipopeptides) was described 30 years ago with the discovery of daptomycin (Debono et al., 1987). However, recently a new class is hypothesised to have been discovered through high-throughput screening of a previously undescribed soil microorganism, Eleftheria terrae. Teixobactin (Ling et al., 2015) has been touted as the first of a new class of antibiotics – the first in 30 years. Its mode of action occurs through binding of multiple non-protein targets, including peptidoglycan precursor lipid II (much like the mode of action of vancomycin) (Ling et al., 2015).
Figure 2: Structures of penicillin and teixobactin. Highlights the increase in complexity in structure required by antibiotics as antibiotic resistance becomes more commonplace.