Spectinamides: a new class of semisynthetic antituberculosis agents that overcome native drug efflux

Abstract

Although the classical antibiotic spectinomycin is a potent bacterial protein synthesis inhibitor, poor antimycobacterial activity limits its clinical application for treating tuberculosis. Using structure-based design, a novel semisynthetic series of spectinomycin analogs was generated with selective ribosomal inhibition and excellent narrow-spectrum antitubercular activity. In multiple murine infection models, these spectinamides were well tolerated, significantly reduced lung mycobacterial burden and increased survival. In vitro studies demonstrated a lack of cross-resistance with existing tuberculosis therapeutics, activity against MDR/XDR-tuberculosis, and an excellent pharmacological profile. Key to their potent antitubercular properties was their structural modification to evade the Rv1258c efflux pump, which is upregulated in MDR strains and is implicated in macrophage induced drug tolerance. The antitubercular efficacy of spectinamides demonstrates that synthetic modifications to classical antibiotics can overcome the challenge of intrinsic efflux pump-mediated resistance and expands opportunities for target based tuberculosis drug discovery.

Synergistic Interactions of Vancomycin with Different Antibiotics against Escherichia coli: Trimethoprim and Nitrofurantoin Display Strong Synergies with Vancomycin against Wild-Type E. coli

“…Thus, some investigators are focusing on natural products derived from nonconventional sources, such as plants (10,11), marine microorganisms (12), and insects (13). Another strategy involves making new chemical derivatives of existing antibiotics, on the basis of the rational design of the compounds using information such as the three-dimensional structure of the antibiotic (14,15), or linking drugs to peptides that can pass through membranes to facilitate their entry into the cell (16).…”

Latent Tuberculosis Infection: Myths, Models, and Molecular Mechanisms

“…Interestingly, the addition of verapamil to the standard anti-TB regimen accelerates bacillary clearance in C3HeB/FeJ mice and significantly lowers relapse rates following 4 months of treatment compared with the case for mice receiving standard therapy alone (305). Recently, semisynthetic analogs of the protein synthesis inhibitor spectinomycin were found to have potent activity against drugsusceptible and drug-resistant M. tuberculosis, at least in part due to chemical modification, which allows the drugs to evade the Rv1258c efflux pump (306).…”

Antituberculosis Agents on the Horizon

“…Cross resistance to TB treatments that inhibit protein synthesis is not observed with these compounds. The compilation of this data suggests the potential use of spectinamides as clinical anti-tubercular agents [11].…”

“…In vivo these compounds display strong potency through their selective activity against the ribosome and ability to avoid pump-mediated efflux by structural modification [11]. This potent anti-tubercular action spans over prototypes of acute and chronic infections, MDR-strains, and XDR-types of tuberculosis.…”