Aminomethyl spectinomycins: a novel antibacterial chemotype for biothreat pathogens.

Abstract

New antibiotics that are active against multi-drug-resistant strains and difficult-to-treat bacterial infections are needed. Synthetic modification of spectinomycin, a bacterial protein synthesis inhibitor, has been shown to increase antibacterial activity compared with spectinomycin. Aminomethyl spectinomycins are active against Gram-negative and Gram-positive bacterial pathogens. In this study, the ability of aminomethyl spectinomycins to treat biothreat pathogens is examined by MIC profiling, synergy testing, and in vivo efficacy experiments. Compound 1950 exhibited potent antibacterial activity against Gram-negative pathogens Brucella spp., Burkholderia mallei, and Francisella tularensis, but showed little to no growth inhibition against Burkholderia pseudomallei, Bacillus anthracis, and Yersinia pestis. Combination testing in checkerboard assays revealed that aminomethyl spectinomycin-antibiotic combinations had mainly an additive effect against the susceptible biodefense pathogens. The in vivo efficacy of compound 1950 was also demonstrated in mice infected with B. mallei (FMH) or F. tularensis (SchuS4). These results suggest that aminomethyl spectinomycins are promising new candidates for development of therapeutics against biodefense bacterial agents.

• Authors: Jennifer M Scarff, Samanthi L Waidyarachchi, Christopher J Meyer, Douglas J Lane, Weirui Chai, Margaret M Lemmon, Jiuyu Liu, Michelle M Butler, Terry L Bowlin, Richard E Lee, Rekha G Panchal
• Journal: The Journal of antibiotics (J Antibiot (Tokyo)) Vol. 72 Issue 9 Pg. 693-701 (09 2019) ISSN: 1881-1469 [Electronic] England
• PMID: 31164713 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Spectinomycin

Topics

• Animals
• Anti-Bacterial Agents (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Bacterial Infections (drug therapy)
• Disease Models, Animal
• Drug Interactions
• Gram-Negative Bacteria (drug effects)
• Gram-Positive Bacteria (drug effects)
• Mice
• Microbial Sensitivity Tests
• Molecular Structure
• Spectinomycin (analogs & derivatives, chemistry, pharmacology, therapeutic use)
• Treatment Outcome