teixobactin and Staphylococcal-Infections

The cyclic depsipeptide, teixobactin, kills a number of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), and Mycobacterium tuberculosis without detectable resistance. To date, teixobactin is the only molecule in its class that has shown in vivo antibacterial efficacy. In this work, we designed and synthesized 10 new in vivo ready teixobactin analogues. These analogues showed highly potent antibacterial activities against Staphylococcus aureus, MRSA, and vancomycin-resistant enterococci (VRE) in vitro. One analogue, d-Arg

Topics: Animals; Depsipeptides; Drug Design; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Keratitis; Methicillin-Resistant Staphylococcus aureus; Mice; Staphylococcal Infections; Staphylococcus aureus; Vancomycin Resistance; Vancomycin-Resistant Enterococci

The discovery of the new antibiotic teixobactin has been timely in the race for unearthing novel antibiotics wherein the emergence of drug resistant bacteria poses a serious threat worldwide. Herein, we present the total syntheses and biological activities of two teixobactin analogues. This approach is simple, efficient and has several advantages: it uses commercially available building blocks (except AllocHN-d-Thr-OH), has a single purification step and a good recovery (22%). By using this approach we have synthesised two teixobactin analogues and established that the d-amino acids are critical for the antimicrobial activity of these analogues. With continuing high expectations from teixobactin, this work can be regarded as a stepping stone towards an in depth study of teixobactin, its analogues and the quest for synthesising similar molecules.

Topics: Anti-Bacterial Agents; Bacteria; Depsipeptides; Escherichia coli; Escherichia coli Infections; Humans; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship

Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.

Topics: Animals; Anti-Bacterial Agents; Betaproteobacteria; Biological Products; Cell Wall; Depsipeptides; Disease Models, Animal; Drug Resistance, Microbial; Female; Mice; Microbial Sensitivity Tests; Microbial Viability; Molecular Sequence Data; Multigene Family; Mycobacterium tuberculosis; Peptidoglycan; Staphylococcal Infections; Staphylococcus aureus; Teichoic Acids; Time Factors