teixobactin and Gram-Positive-Bacterial-Infections

Over the past two decades infections due to antibiotic-resistant bacteria have escalated world-wide, affecting patient morbidity, mortality, and health care costs. Among these bacteria, Enterococcus faecium and Enterococcus faecalis represent opportunistic nosocomial pathogens that cause difficult-to-treat infections because of intrinsic and acquired resistance to a plethora of antibiotics. In recent years, a number of novel antimicrobial compound classes have been discovered and developed that target Gram-positive bacteria, including E. faecium and E. faecalis. These new antibacterial agents include teixobactin (targeting lipid II and lipid III), lipopeptides derived from nisin (targeting lipid II), dimeric vancomycin analogues (targeting lipid II), sortase transpeptidase inhibitors (targeting the sortase enzyme), alanine racemase inhibitors, lipoteichoic acid synthesis inhibitors (targeting LtaS), various oxazolidinones (targeting the bacterial ribosome), and tarocins (interfering with teichoic acid biosynthesis). The targets of these novel compounds and mode of action make them very promising for further antimicrobial drug development and future treatment of Gram-positive bacterial infections. Here we review current knowledge of the most favorable anti-enterococcal compounds along with their implicated modes of action and efficacy in animal models to project their possible future use in the clinical setting.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Cell Membrane; Cell Wall; Cross Infection; Depsipeptides; Drug Discovery; Drug Resistance, Multiple, Bacterial; Enterococcus; Enterococcus faecalis; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Models, Animal; Nisin; Vancomycin

It looks that a new era of antimicrobial peptides (AMPs) started with the discovery of teixobactin, which is a "head to side-chain" cyclodepsipeptide. It was isolated from a soil gram-negative b-proteobacteria by means of a revolutionary technique. Since there, several groups have developed synthetic strategies for efficient synthesis of this peptide and its analogues as well. Herein, all chemistries reported as well as the biological activity of the analogues are analyzed. Finally, some inputs regarding new trends for the next generation of analogues are discussed.

Topics: Anti-Infective Agents; Depsipeptides; Gram-Negative Bacteria; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Proteobacteria; Soil Microbiology; Solid-Phase Synthesis Techniques; Structure-Activity Relationship

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

Topics: Anti-Bacterial Agents; Depsipeptides; Drug Resistance, Bacterial; Gram-Positive Bacterial Infections; Humans; Tuberculosis