Vol.:(0123456789) 1 3 International Journal of Peptide Research and Therapeutics https://doi.org/10.1007/s10989-018-9690-0 Bactericidal Potency and Extended Serum Life of Stereo-Chemically Engineered Peptides Against Mycobacterium Prakash Kishore Hazam 1  · Anjali Singh 1  · Nitin Chaudhary 1  · Vibin Ramakrishnan 1 Accepted: 8 March 2018 © Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Tuberculosis is one of the leading causes of death, with an annual mortality rate of 2 million. The present treatment regi- men for Mycobacterium species is strenuous, extending up to 12 months. Even then, rise of antibiotic resistance has limited the prognosis, with increased instances of multidrug resistant (MDR–TB) and extremely drug resistant (XDR–TB) cases reported. Peptide based antibiotics can be an efective solution due to their low toxicity, biocompatibility and predictable metabolism, but has not been employed due to their short plasma half life. In this brief communication, we demonstrate the bactericidal potency of cationic amphipathic peptides as an efective bactericidal agent against Mycobacterium smegmatis. Potency of stereo-engineered LDLD or DLDL peptides have been retained their potency, while their poly L variants rapidly lost their activity, when the experiment was repeated in human serum. To establish this as a design strategy, we further veri- fed the results by repeating the experiment in a gram negative bacteria E. coli. One of the designed peptides were showing a minimum inhibitory concentration (MIC) value as low as 3.13 µM, suggesting the possibility of future development as a therapeutic peptide. Keywords Chain stereochemistry · Plasma half-life · Antimicrobial peptide · Minimum inhibitory concentration · Mycobacterium · E. coli Introduction Tuberculosis (TB) is one of the top 10 causes of death (Car- ranza-Rosales et al. 2017), with more than 10 million cases reported every year and among them, approximately 2 mil- lion patients succumb to the disease (Sandhu 2011; Beg et al. 2017). Mycobacterium tuberculosis (Mtb), is the causa- tive agent, which parasitizes human macrophages for its sus- tainability and proliferation (Estrella et al. 2011). Increase in drug resistance is a major challenge to the disease control mechanisms presently in place (Podinovskaia et al. 2013). Even for the drug susceptible TB, the present treatment regi- men is onerous (Zuniga et al. 2015), and hence there is an urgent clinical need for the discovery of new chemical enti- ties efective for both drug susceptible and resistant TB. Peptide based antimicrobials have been recognized as a safe and efective option, with increased selectivity and tol- erance (Paterson et al. 2017; Jaskiewicz et al. 2016; Arakha et al. 2016; Ravichandran et al. 2016; Kaur et al. 2008; Koh et al. 2015). But usage of peptides as a therapeutic agent was limited by short plasma half-life (Molchanova et al. 2017) and negligible oral bio-availability (Di 2015). The shorter half-life is due to numerous peptidases and excretory mechanisms that inactivate and clear peptides from the sys- tem (Di 2015; Yeaman and Yount 2003). Several techniques for extending plasma half-life have been developed, such as stapling and clipping of peptide sequences, cyclization, binding to albumin and Polyethylene glycol (PEGylation) (Fosgerau and Hofmann 2015) etc. Limitations of endog- enous peptides have motivated researchers to focus on the design of peptide analogs, short sequence oligopeptides and innovative delivery systems. Recently Henry et al. reported a subcutaneous implantable osmotic pump system that deliv- ers peptide continuously up to one year for the treatment of type 2 diabetes (Henry et al. 2014). Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10989-018-9690-0) contains supplementary material, which is available to authorized users. * Vibin Ramakrishnan vibin@iitg.ernet.in 1 Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781 039, India