Acyldepsipeptide Analogues: A Future Generation Antibiotics for Tuberculosis Treatment

Abstract

Acyldepsipeptides (ADEPs) are a new class of emerging antimicrobial peptides (AMPs), which are currently explored for treatment of pathogenic infections, including tuberculosis (TB). These cyclic hydrophobic peptides have a unique bacterial target to the conventional anti-TB drugs, and present a therapeutic window to overcome Mycobacterium Tuberculosis (M. tb) drug resistance. ADEPs exerts their antibacterial activity on M. tb strains through activation of the protein homeostatic regulatory protease, the caseinolytic protease (ClpP1P2). ClpP1P2 is normally regulated and activated by the ClpP-ATPases to degrade misfolded and toxic peptides and/or short proteins. ADEPs bind and dysregulate all the homeostatic capabilities of ClpP1P2 while inducing non-selective proteolysis. The uncontrolled proteolysis leads to M. tb cell death within the host. ADEPs analogues that have been tested possess cytotoxicity and poor pharmacokinetic and pharmacodynamic properties. However, these can be improved by drug design techniques. Moreover, the use of nanomaterial in conjunction with ADEPs would yield effective synergistic effect. This new mode of action has potential to combat and eradicate the extensive multi-drug resistance (MDR) problem that is currently faced by the public health pertaining bacterial infections, especially TB.

Knockout Mouse Studies Show That Mitochondrial CLPP Peptidase and CLPX Unfoldase Act in Matrix Condensates near IMM, as Fast Stress Response in Protein Assemblies for Transcript Processing, Translation, and Heme Production

“…This research area is rapidly advancing and holds great promise for the treatment of cancer and infections. While the authors are no experts in this field, we recommend several innovative reviews and articles produced over the past 10 years on CLPP-modulating drug compounds [ 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 ] and relevant structure/binding studies [ 45 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , 241 , 242 , 243 , 244 ] for further reading. A better understanding of CLPXP-dependent UPRmt will also help clarify how extra-mitochondrial signals (such as extruded mt-dsRNA, perhaps mtRNA-G4, and associated ribonucleoproteins) trigger responses of the nucleus and the endoplasmic reticulum UPR, a basic research field where mechanisms are investigated in yeast and nematodes but are poorly defined in mammals at present [ 41 , 245 , 246 , 247 , 248 , 249 , 250 ].…”

Antibiotic Resistance to Mycobacterium tuberculosis and Potential Use of Natural and Biological Products as Alternative Anti-Mycobacterial Agents

“…Of note, LL-37 stimulation of infected macrophages led to the production of anti-inflammatory cytokines, IL-10 and TGF-beta, thus, suggesting a modulation of the immune response in the earlier phase of Mtb infection [ 120 ]. Among analogues of AMPs, acyl depsipeptides (ADEPs) seem to represent a future generation of antibiotics against tuberculosis [ 121 ]. ADEPs exert antibacterial activity on Mtb strains through activation of the caseinolytic protease ClpP1P2.…”