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Bacterial resistance to existing drugs is becoming a serious public health issue, urging extensive search for new antibiotics. Teixobactin, a cyclic depsipeptide discovered in a screen of uncultured bacteria, shows potent activity against all the tested Gram-positive bacteria. Remarkably, no teixobactin-resistant bacterial strain has been obtained despite extensive efforts, highlighting the great potential of teixobactin as a lead compound in the fight against antimicrobial resistance (AMR). This review summarizes recent progresses in the understanding of many aspects of teixobactin, including chemical structure, biological activity, biosynthetic pathway, and mode of action. We also discuss the different synthetic strategies in producing teixobactin and its analogues, and the structure–activity relationship (SAR) studies.

Teixobactin is a cyclic depsipeptide exhibiting potent activity against all the tested Gram-positive bacteria. Remarkably, thus far no teixobactin-resistant bacterial strain has been obtained despite extensive efforts. This Review discusses recent progress in the understanding of many aspects of teixobactin, including biological activity, biosynthetic pathway, mode of action, and the structure–activity relationship studies.

Bacterial cell wall synthesis is the target for some of our most powerful antibiotics and has thus been the subject of intense research focus for more than 50 years. Surprisingly, we still lack a fundamental understanding of how bacteria build, maintain and expand their cell wall. Due to technical limitations, directly testing hypotheses about the coordination and biochemistry of cell wall synthesis enzymes or architecture has been challenging, and interpretation of data has therefore often relied on circumstantial evidence and implicit assumptions. A number of recent papers have exploited new technologies, like single molecule tracking and real-time, high resolution temporal mapping of cell wall synthesis processes, to address fundamental questions of bacterial cell wall biogenesis. The results have challenged established dogmas and it is therefore timely to integrate new data and old observations into a new model of cell wall biogenesis in rod-shaped bacteria.

The cell wall is an essential component of most bacterial cells, and has been a major focus of research for the last 50 years. Despite this intense research, we still have an incomplete understanding of how bacteria construct their cell wall. In this MicroReview, we will summarize important new data generated in the last few years, reexamine some established ideas in the field and propose a new model of cell wall biogenesis in rod-shaped bacteria.

The peptidoglycan is a rigid matrix required to resist turgor pressure and to maintain the cellular shape. It is formed by linear glycan chains composed of N-acetylmuramic acid-(β-1,4)-N-acetylglucosamine (MurNAc-GlcNAc) disaccharides associated through cross-linked peptide stems. The peptidoglycan is continually remodelled by synthetic and hydrolytic enzymes and by chemical modifications, including O-acetylation of MurNAc residues that occurs in most Gram-positive and Gram-negative bacteria. This modification is a powerful strategy developed by pathogens to resist to lysozyme degradation and thus to escape from the host innate immune system but little is known about its physiological function. In this study, we have investigated to what extend peptidoglycan O-acetylation is involved in cell wall biosynthesis and cell division of Streptococcus pneumoniae. We show that O-acetylation driven by Adr protects the peptidoglycan of dividing cells from cleavage by the major autolysin LytA and occurs at the septal site. Our results support a function for Adr in the formation of robust and mature MurNAc O-acetylated peptidoglycan and infer its role in the division of the pneumococcus.

In this study, we have investigated to what extend peptidoglycan O-acetylation is involved in cell wall biosynthesis and cell division of Streptococcus pneumoniae. We show that O-acetylation driven by Adr protects the peptidoglycan of dividing cells from cleavage by the major autolysin LytA and occurs at the septal site. Our results support a function for Adr in the formation of robust and mature MurNAc O-acetylated peptidoglycan and infer its role in the division of the pneumococcus.

The cell wall envelope of mycobacteria is structurally distinct from that of both Gram-positive and Gram-negative bacteria. In Mycobacterium tuberculosis, this cell wall has unique structural features and plays a crucial role in drug resistance and macrophage survival under stress conditions. Peptidoglycan is the major constituent of this cell wall, with an important structural role, giving structural strength, and counteracting the osmotic pressure of the cytoplasm. Synthesis of this complex polymer takes place in three stages that occur at three different locations in the cell, from the cytoplasm to the external side of the cell membrane, where polymerization occurs. A fine balance of peptidoglycan synthesis and degradation is responsible for a plethora of molecular mechanisms which are key to the pathogenicity of M. tuberculosis. Enlargement of mycobacterial cells can occur through the synthesis of new peptidoglycan, autolysis of old peptidoglycan, or a combination of both processes. Here, we discuss the chemical aspects of peptidoglycan synthesis and degradation, in relation to metabolic stages of M. tuberculosis. Going from inside the mycobacterial cytoplasm to outside its membrane, we describe the assembly line of peptidoglycan synthesis and polymerization, and continue with its depolymerization events and their consequences on mycobacterial life and resuscitation from dormancy.

Mycobacterial Peptidoglycan Cell Wall Turnover: A complex assembly line is responsible for the Peptidoglycan wall construction, from the synthesis of Park's nucleotide synthesis inside the cytoplasm to Peptidoglycan polymerization in the periplasmic space. In resuscitation from mycobacterial dormancy, the wall is attacked by RipA and Rpf hydrolases, which produce free muropeptide sensors and wake up mycobacteria from a dormant “comfortably numb” state.

Most bacteria possess a peptidoglycan cell wall that determines their morphology and provides mechanical robustness during osmotic challenges. The biosynthesis of this structure is achieved by a large set of synthetic and lytic enzymes with varying substrate specificities. Although the biochemical functions of these proteins are conserved and well-investigated, the precise roles of individual factors and the regulatory mechanisms coordinating their activities in time and space remain incompletely understood. Here, we comprehensively analyze the autolytic machinery of the alphaproteobacterial model organism Caulobacter crescentus, with a specific focus on LytM-like endopeptidases, soluble lytic transglycosylases and amidases. Our data reveal a high degree of redundancy within each protein family but also specialized functions for individual family members under stress conditions. In addition, we identify two lytic transglycosylases and an amidase as new divisome components that are recruited to midcell at distinct stages of the cell cycle. The midcell localization of these proteins is affected by two LytM factors with degenerate catalytic domains, DipM and LdpF, which may serve as regulatory hubs coordinating the activities of multiple autolytic enzymes during cell constriction and fission respectively. These findings set the stage for in-depth studies of the molecular mechanisms that control peptidoglycan remodeling in C. crescentus.

Peptidoglycan biosynthesis is mediated by a variety of synthetic and lytic enzymes, whose roles and regulation remain incompletely understood. Here, we comprehensively analyze the autolytic machinery of the alphaproteobacterium Caulobacter crescentus. Our study pinpoints factors critical for viability under stress conditions and identifies three more divisome-associated lytic enzymes. Moreover, it reveals two LytM factors with degenerate catalytic domains as regulatory hubs coordinating the activities of multiple peptidoglycan hydrolases during cell constriction and fission respectively.