Activity of Tricyclic Pyrrolopyrimidine Gyrase B Inhibitor against Mycobacterium abscessus

Abstract

Tricyclic pyrrolopyrimidines (TPPs) are a new class of antibacterials inhibiting the ATPase of DNA gyrase. TPP8, a representative of this class, is active against Mycobacterium abscessus in vitro .

Why Matter Matters: Fast-Tracking Mycobacterium abscessus Drug Discovery

“…Further optimization produced analogs that inhibited the M. tuberculosis DNA gyrase and were active against drug-resistant TB strains [ 89 , 90 ]. From this series, TPP8 was evaluated for anti- M. abscessus activity ( Table 1 ) [ 36 ]. TPP8 had potent activity against M. abscessus reference strains and clinical isolates representing all three subspecies [ 36 ].…”

“…From this series, TPP8 was evaluated for anti- M. abscessus activity ( Table 1 ) [ 36 ]. TPP8 had potent activity against M. abscessus reference strains and clinical isolates representing all three subspecies [ 36 ]. In fact, this compound was more potent against M. abscessus than two other gyrase inhibitors, moxifloxacin and SPR719 [ 36 ].…”

“…TPP8 had potent activity against M. abscessus reference strains and clinical isolates representing all three subspecies [ 36 ]. In fact, this compound was more potent against M. abscessus than two other gyrase inhibitors, moxifloxacin and SPR719 [ 36 ]. TPP8 inhibited the supercoiling activity of M. abscessus DNA gyrase in vitro, and in vitro generated M. abscessus TPP8-resistant strains had mutations in the ATPase domain of GyrB, confirming the drug’s target and mechanism of action [ 36 ].…”

“…In fact, this compound was more potent against M. abscessus than two other gyrase inhibitors, moxifloxacin and SPR719 [ 36 ]. TPP8 inhibited the supercoiling activity of M. abscessus DNA gyrase in vitro, and in vitro generated M. abscessus TPP8-resistant strains had mutations in the ATPase domain of GyrB, confirming the drug’s target and mechanism of action [ 36 ]. TPP8 also inhibited the intracellular growth of M. abscessus in macrophages [ 36 ].…”

“…TPP8 inhibited the supercoiling activity of M. abscessus DNA gyrase in vitro, and in vitro generated M. abscessus TPP8-resistant strains had mutations in the ATPase domain of GyrB, confirming the drug’s target and mechanism of action [ 36 ]. TPP8 also inhibited the intracellular growth of M. abscessus in macrophages [ 36 ]. Due to TPP8’s lack of oral bioavailability, intraperitoneal administration was used to evaluate the compound’s in vivo efficacy in NOD SCID mice [ 36 ].…”