Peptidoglycan Muropeptides: Release, Perception, and Functions as Signaling Molecules

Abstract

Peptidoglycan (PG) is an essential molecule for the survival of bacteria, and thus, its biosynthesis and remodeling have always been in the spotlight when it comes to the development of antibiotics. The peptidoglycan polymer provides a protective function in bacteria, but at the same time is continuously subjected to editing activities that in some cases lead to the release of peptidoglycan fragments (i.e., muropeptides) to the environment. Several soluble muropeptides have been reported to work as signaling molecules. In this review, we summarize the mechanisms involved in muropeptide release (PG breakdown and PG recycling) and describe the known PG-receptor proteins responsible for PG sensing. Furthermore, we overview the role of muropeptides as signaling molecules, focusing on the microbial responses and their functions in the host beyond their immunostimulatory activity.

Inhibitors of Bacterial Swarming Behavior

“…While cefotaxime (23), ciprofloxacin (24)a nd trimethoprim inhibited polar-chemoreceptora rray assembly of S. enterica (ser.T yphimurium) that is essential for swarming, chloramphenicol inhibited swarming by ad ecrease in flagellation (Scheme 2). [81] Many furthera ntibiotic classes have been linked to regulatory effects on bacterial behavior at sublethal concentrations. [75c] For example, also the aminoglycoside gentamicin, like azithromycin (21), reduced lasI/lasR and rhlI/rhlR expression and AHL productioni nP.…”

“…In some cases, like amikacin, swarming inhibition even seems to be species specific. [81,82] Although the mechanismsb y which antibiotics in low concentrations inhibit swarming behavior are so far not conclusively understood, targeting of quorum sensing as well as direct interference with the regulation of flagellar gene expression or flagellar integrity are likely central concepts.A ntibiotics also may lead to long-term regulatory changes in bacterial cells which have been pre-exposed for extended time to sublethal concentrationso fa ntibiotics. For example, pretreatment of E. coli with approximately 1 mm ( 1 = 2 MIC)g entamicin through downregulation of succinate dehydrogenase (sdh)g enes inhibited swarming but not swimming motility in af umarate-dependent manner.…”

Dynamic expression of intra‐ and extra‐cellular proteome and the influence of epiphytic bacteria for Nostoc flagelliforme in response to rehydration

“…It is well documented that many microorganisms exit dormancy in response to cell wall muropeptides (Dworkin and Shah, 2010). First and most importantly, we address the possibility that one signal of such condition is the release of cell wall muropeptides by hydrolysis process in the extracellular, which subsequently serve as a 'wake-up call' and stimulate the recovery of dormant cells through modification of the translation apparatus (Dworkin and Shah, 2010;Irazoki et al, 2019). As shown in Fig.…”

“…The digest PG fragments such as muropeptide can be either transported into the cytoplasm through PG transporters or released to the environment. Once in the cytosol, PG fragments might enter be reincorporated into the newly polymerized PG mesh or used as an energy source by the cell (Raghavendra et al, 2018;Squeglia et al, 2018;Irazoki et al, 2019). The PG-turnover products released to the environment are detected by other cells and can act as signalling molecules.…”

Facile Synthesis and Metabolic Incorporation ofm-DAP Bioisosteres Into Cell Walls of Live Bacteria

“…Therefore, it is critically important to be able to synthesize homogeneous m-DAP based PG fragments (as opposed to heterogenous isolated PG fragments from live bacteria) to systematically dissect the biological consequences of alterations to the PG stem peptide found in these organisms. 13,14 While Fmoc-protected L-Lys building blocks are readily available and highly compatible with standard solid phase peptide chemistry, m-DAP is not commercially available and this poses a significant synthetic barrier. The internal symmetry of m-DAP coupled with the need to have differentiated, orthogonally protected stereocenters, makes its synthesis and that of its protected counterparts highly challenging.…”