Discovery, Synthesis, and Optimization of Peptide-Based Antibiotics.

The rise of multidrug resistant bacteria has significantly compromised our supply of antibiotics and poses an alarming medical and economic threat to society. To combat this problem, it is imperative that new antibiotics and treatment modalities be developed, especially those toward which bacteria are less capable of developing resistance. Peptide natural products stand as promising candidates to meet this need as bacterial resistance is typically slow in response to their unique modes of action. They also have additional benefits including favorable modulation of host immune responses and often possess broad-spectrum activity against notoriously treatment resistant bacterial biofilms. Moreover, nature has provided a wealth of peptide-based natural products from a range of sources, including bacteria and fungi, which can be hijacked in order to combat more dangerous clinically relevant infections.This Account highlights recent advances in the total synthesis and development of a range of peptide-based natural product antibiotics and details the medicinal chemistry approaches used to optimize their activity.In the context of antibiotics with potential to treat Gram-positive bacterial infections, this Account covers the synthesis and optimization of the natural products daptomycin, glycocin F, and alamethicin. In particular, the reported synthesis of daptomycin highlights the utility of on-resin ozonolysis for accessing a key kynurenine residue from the canonical amino acid tryptophan. Furthermore, the investigation into glycocin F analogues uncovered a potent lead compound against Lactobacillus plantarum that bears a non-native thioacetal linkage to a N-acetyl-d-glucosamine (GlcNAc) sugar, which is otherwise O-linked in its native form.For mycobacterial infections, this Account covers the synthesis and optimization of teixobactin, callyaerin A, lassomycin, and trichoderin A. The synthesis of callyaerin A, in particular, highlighted the importance of a (Z)-2,3-diaminoacrylamide motif for antimicrobial activity against Mycobacterium tuberculosis, while the synthesis of trichoderin A highlighted the importance of (R)-stereoconfiguration in a key 2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid (AHMOD) residue.Lastly, this Account covers lipopeptide antibiotics bearing activity toward Gram-negative bacterial infections, namely, battacin and paenipeptin C. In both cases, optimization of the N-terminal lipid tails led to the identification of analogues with potent activity toward Escherichia coli and Pseudomonas aeruginosa.

A Versatile Boc Solid Phase Synthesis of Daptomycin and Analogues Using Site Specific, On-Resin Ozonolysis to Install the Kynurenine Residue.

A de novo solid-phase synthesis of the cyclic lipodepsipeptide daptomycin via Boc chemistry was achieved. The challenging ester bond formation between the nonproteinogenic amino acid kynurenine was achieved by esterification of a threonine residue with a protected tryptophan. Subsequent late-stage on-resin ozonolysis, inspired by the biomimetic pathway, afforded the kynurenine residue directly. Synthetic daptomycin possessed potent antimicrobial activity (MIC100 =1.0 µg mL-1 ) against S. aureus, while five other daptomycin analogues containing (2R,3R)-3-methylglutamic acid, (2S,4S)-4-methylglutamic acid or canonical glutamic acid at position twelve prepared using this new methodology were all inactive, clearly establishing that the (2S,3R)-3-methylglutamic acid plays a key role in the antimicrobial activity of daptomycin.

Activity of vancomycin, ciprofloxacin, daptomycin and linezolid against coagulasenegative staphylococci bacteremia

Objetivo. Las infecciones por Staphylococcus coagulasa negativos (CNS) resistentes a meticilina aumentado considerablemente en los pacientes hospitalizados. Hemos estudiado la actividad de vancomicina, ciprofloxacino, daptomicina y linezolid en cepas de CNS resistente a meticilina aisladas en hemocultivos clínicamente significativos. Material y Métodos. Se estudiaron 87 cepas de distintas especies de CNS de hemocultivos positivos. Los estafilococos fueron identificados mediante el sistema automático MicroScan Walkaway (Dade Behring, Siemens) y con Api ID 32 Staph (Bio- Merieux, Francia). La sensibilidad a oxacilina, vancomicina y ciprofloxacino fue realizada por dicho sistema MicroScan. La susceptibilidad frente a daptomicina y linezolid fue realizada mediante Etest (AB BioMerieux, Solna, Suecia). Para los criterios de interpretación se siguieron las indicaciones del CLSI. Resultados. Se estudiaron 87 cepas, 55 (63%) fueron S. epidermidis, 15 (17%) fueron S. haemolyticus, 10 (12%) fueron S. hominis, y 7 (8%) pertenecieron a otras especies. 53 (61%) cepas presentaron una MIC para vancomicina de 2 mg/L. La resistencia a ciprofloxacino, MIC > 2 mg/L fue observada en 56 (64%) cepas. No se encontraron resistencia a daptomicina, con un rango de sensibilidad entre 0.032-1 mg/L y un valor modal de 0,25 mg/L. Se aislaron 10 (11,5%) cepas resistentes a linezolid. Nueve pacientes estuvieron ingresados en la Unidad de Cuidados Intensivos, donde la estancia media fue de 38 días (rango 16-58 días), y uno perteneció al Servicio de Cirugía Hepato-Pancreática, con una estancia de 64 días. Conclusiones. Es frecuente aislar cepas de CNS con pérdida de sensibilidad para vancomicina en nuestro hospital, mientras que daptomicina presenta una alta sensibilidad frente a este tipo de microorganismos. El uso masivo y continuado de linezolid ha llevado a la aparición de resistencias(AU)

Objective. Multiresistant coagulase-negative staphylococci (CNS) infections are mainly increased in hospitalized patients. We have studied the activity of vancomycin, ciprofloxacin, daptomycin and linezolid in methicillin-resistant CNS strains, isolated from true blood cultures. Methods. We collected 87 strains of different CNS species from positive blood cultures. Staphylococci were identified by MicroScan Walkaway (Dade Behring, Siemens) and with the Api ID 32 Staph (BioMerieux, France). The susceptibility to oxacillin, vancomycin and ciprofloxacin was performed by automatic microdilution plate as cited above. The susceptibility to daptomycin and linezolid was performed by Etest (AB BioMerieux, Solna, Sweden). Interpretative criteria were done following the CLSI guidelines. Results. Eighty-seven CNS strains were studied: 55 (63%) were S. epidermidis, 15 (17%) S. haemolyticus, 10 (12%) S. hominis, and 7 (8%) other species. Fifty-three (61%) strains showed loss of susceptibility to vancomycin, MIC = 2 mg/L. Ciprofloxacin resistance, MIC > 2 mg/L, was observed in 56 (64%) strains. Daptomycin resistance was not observed, with a susceptibility range between 0.032-1 mg/L and modal value of 0.25 mg/L. Ten strains (11.5%) resistant to linezolid were observed. Nine patients were in ICU, where the average length of stay was 38 days (range 16- 58 days) and one belonged to Hepato-Pancreatic Surgery, where he stayed for 64 days. Conclusions. Low susceptibility to vancomycin is frecuent in the CNS strains studied in our hospital. Daptomycin shows a high efficacy against CNS, and it could be useful for the treatment of primary bacteremia or catheter associated bacteremia. The massive and continuous use of linezolid has led to the appearance of resistance(AU)