Isolation, structure, and antibacterial activities of lucensimycins D-G, discovered from Streptomyces lucensis MA7349 using an antisense strategy.
Bacterial resistance to existing antibiotics continues to grow, necessitating the discovery of new compounds of this type. Antisense-based whole-cell target-based screening is a new and highly sensitive antibiotic discovery approach that has led to a number of new natural product antibiotics. Screening with a rpsD-sensitized strain led to the discovery of a number of natural product polyketides from Streptomyces lucensis. Complete workup of the fermentation extract of this strain allowed for the isolation of seven new compounds, lucensimycins A-G (1-3, 4a, 5-7), with varying degrees of antibacterial activities. Lucensimycin E (5) exhibited the best activity and showed MIC values of 32 microg/mL against Staphylococcus aureus and 8 microg/mL against Streptococcus pneumoniae. The isolation, structure elucidation, and antibacterial activities of four new members, lucensimycins D-G, are described. Lucensimycins D (4a) and E (5) are N-acetyl-l-cysteine adducts of lucensimycin A (1). Semisynthesis of lucensimycins D and E from lucensimycin A has also been described. Lucensimycins F and G are myo-inositolyl-alpha-2-amino-2-deoxy-l-idosyl amide derivatives of lucensimycins D and E, respectively. The relative configuration of these compounds was determined, in part, by molecular dynamics simulations.
Singh
Sheo B
SB
Merck Research Laboratories, Rahway, New Jersey 07065, USA. sheo_singh@merck.com
Zink
Deborah L
DL
Dorso
Karen
K
Motyl
Mary
M
Salazar
Oscar
O
Basilio
Angela
A
Vicente
Francisca
F
Byrne
Kevin M
KM
Ha
Sookhee
S
Genilloud
Olga
O
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D016373:DNA, Antisense / Q000235:genetics; D004269:DNA, Bacterial / Q000235:genetics*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013141:Spiro Compounds / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013302:Streptomyces / Q000737:chemistry* / Q000235:genetics*; D014900:West Indies
D000900:Anti-Bacterial Agents; D016373:DNA, Antisense; D004269:DNA, Bacterial; D013141:Spiro Compounds; C522747:lucensimycin A