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.
Highlights
The rate of emergence of antibiotic-resistant pathogens is outpacing the development of novel antimicrobial agents [1]
AmSPCs are active against B. mallei, Brucella spp., and F. tularensis
The MICs were determined for four aminomethyl spectinomycins (amSPCs) against panels of representative isolates of B. mallei, Brucella spp., F. tularensis, B. anthracis, and B. pseudomallei
Summary
The rate of emergence of antibiotic-resistant pathogens is outpacing the development of novel antimicrobial agents [1]. Previous work has demonstrated that spectinomycins with amide modifications on the 3′ position, called “spectinamides” (Fig. 1a), have increased activity against multi-drug-resistant strains of Mycobacterium tuberculosis. Critical to this series is the addition of a pyridyl side-chain motif that enables the spectinamide to avoid the Rv1258c efflux pump [6, 7]. The new spectinomycin analogs had improved activity, they were not active against all drug-resistant strains of N. gonorrhoeae. This clearly demonstrates that modification of spectinomycin can result in more potent broad-spectrum antibiotics, and that both the amSPCs and. Treatment with an amSPC led to an increased survival rate of mice infected with B. mallei or F. tularensis
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