New Therapeutic Option for the Treatment of Drug-resistant Bacteria

Older antibiotic agents, such as penicillin, vancomycin, and oxacillin, show decreased potency due to overuse and the subsequent emergence of drug-resistant bacteria. This antimicrobial resistance has been predicted to have enormous consequences for human health, necessitating the development of new agents in the ongoing war between humans and the germs that attack us.

The recent discovery of one such agent, teixobactin,¹ should provide clinicians with a new therapeutic option for the treatment of drug-resistant bacteria. The discovery of teixobactin is particularly timely and exciting, as there have been no signs of resistance to the bacteria it is known to work against. Also, it has been shown to attack bacteria in multiple ways,² which suggests that resistance may not occur anytime soon. The results of a study published in Chemical Communications show that it is possible to synthesize analogs of this new antibiotic using a simple, efficient approach.³

According to the lead author on the publication, Anish Parmar of the School of Pharmacy at the University of Lincoln in the United Kingdom, the objectives of the study were to synthesize and characterize teixobactin analogs based on its already known structural complexity as determined by nuclear magnetic resonance and liquid chromatography—mass spectrometry.

A key barrier to the simple and efficient synthesis of teixobactin analogs stems from the presence of non-natural amino acids in its structure, one of which is L-allo-enduracididine. Because this enduracididine amino acid is not commercially available, total synthesis of teixobactin has been described as a time-consuming endeavor.⁴ To overcome this challenge, Parmar and colleagues replaced this non-naturally occurring amino acid with the commercially available natural amino acid arginine, regarded as the closest structural match suitable for the replacement of the L-allo-enduracididine.

The majority of the report is dedicated to the complex organic chemistry experiments conducted in order to synthesize the two teixobactin analogs, referred to as analog 1 and analog 3 in the publication. Perhaps the most interesting and important part of this description pertained to the synthesis of a new building block, AllocHN-D-Thr-OH, that allowed Parmar et al to synthesize the teixobactin analogs completely on solid phase with only a single purification required after final cleavage.

Parmar and colleagues noted several advantages of the methodological approach they developed during the course of their work, describing it as simple and efficient. Additionally, it allows for the use of commercially available building blocks, with the exception of the building block they developed. Furthermore, it requires only a single purification step and results in a good recovery (22%).

Beyond the description of these approaches, Parmar et al also presented the results of further experiments describing their antibacterial activity. Similar to teixobactin, analog 1 was found to be active against both Gram-positive and Gram-negative bacteria. Analog 3, however, only demonstrated activity against Gram-positive bacteria. In a comparison of their activity on Gram-positive bacteria, Parmar and colleagues found analog 1 to be 64 times more effective than analog 3. Because the key difference between the analogs was the presence (analog 1) or absence (analog 3) of three D-amino acids residues, Parmar et al concluded that these three D-amino acids residues were critical for antibacterial activity.

In describing the broader implications of their findings, Parmar and colleagues stated, "The methodology described here is not specific to only one molecule, but it can also be used as a general strategy for synthesis of other analogues of teixobactin." Therefore, the results presented in this publication may represent a pivotal step towards addressing the larger issue of managing patients with bacterial infections associated with antimicrobial resistance.

William Perlman, PhD, CMPP is a former research scientist currently working as a medical/scientific content development specialist. He earned his BA in Psychology from Johns Hopkins University, his PhD in Neuroscience at UCLA, and completed three years of postdoctoral fellowship in the Neuropathology Section of the Clinical Brain Disorders Branch of the National Institute of Mental Health.

References

1. Ling LL, Schneider T, Peoples AJ, et al. A new antibiotic kills pathogens without detectable resistance. Nature 2015;517:455—9.
2. von Nussbaum F, Süssmuth RD. Multiple attack on bacteria by the new antibiotic teixobactin. Angew Chem Int Ed Engl. 2015;54:6684—6.
3. Parmar A, Iyer A, Vincent CS, et al. Efficient total syntheses and biological activities of two teixobactin analogues. Chem Commun (Camb) 2016;52:6060—3.
4. Craig W, Chen J, Richardson D, Thorpe R, Yuan Y. A Highly Stereoselective and Scalable Synthesis of L-allo-Enduracididine. Org Lett 2015;17:4620—3.