Synergistic Activity of Nitroimidazole-Oxazolidinone Conjugates against Anaerobic Bacteria

Abstract

The introductions of the bicyclic 4-nitroimidazole and the oxazolidinone classes of antimicrobial agents represented the most significant advancements in the infectious disease area during the past two decades. Pretomanid, a bicyclic 4-nitroimidazole, and linezolid, an oxazolidinone, are also part of a combination regimen approved recently by the US Food and Drug Administration for the treatment of pulmonary, extensively drug resistant (XDR), treatment-intolerant or nonresponsive multidrug-resistant (MDR) Mycobacterium tuberculosis (TB). To identify new antimicrobial agents with reduced propensity for the development of resistance, a series of dual-acting nitroimidazole-oxazolidinone conjugates were designed, synthesized and evaluated for their antimicrobial activity. Compounds in this conjugate series have shown synergistic activity against a panel of anaerobic bacteria, including those responsible for serious bacterial infections.

Profiling Pretomanid as a Therapeutic Option for TB Infection: Evidence to Date

“…When tested on a panel of anaerobic bacterial species including gram-positive, gram-negative and microaerophilic, pretamonid was largely ineffective with MIC ranging from 2 to >32. 39 Pretamonid, and the structurally similar metronidazole, were similarly ineffective against H. pylori in this in vitro panel. Given that metronidazole is an effective clinical tool against anaerobic infections, these data should be interpreted with caution.…”

Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activity against Microaerophilic and Anaerobic Bacterial Pathogens

“…15−17 The strategy of stably conjugating two different antimicrobial pharmacophores in a single molecular entity, as exemplified by TNP-2092, 15 provides important advantages over the alternative strategy of combining currently approved antimicrobial agents into combination regimens, including matched pharmacokinetics, matched tissue distribution, and as exemplified herein, the potential for mechanism-based synergy. 20,21 Rifamycins are an important class of antibacterial agents 22,23 exhibiting antibacterial activity by inhibiting bacterial RNAP. 24−27 Rifamycins inhibit bacterial RNAP by binding to a site on bacterial RNAP (Rif binding pocket) located adjacent to the RNAP active center and preventing short, 2-3 nucleotide RNA products from being extended to yield longer RNA transcripts.…”

“…The strategy of stably conjugating two different antimicrobial pharmacophores in a single molecular entity, as exemplified by TNP-2092, provides important advantages over the alternative strategy of combining currently approved antimicrobial agents into combination regimens, including matched pharmacokinetics, matched tissue distribution, and as exemplified herein, the potential for mechanism-based synergy. , …”

A Potent Antibiotic Combination of Linezolid and Polymycin B Nonapeptide Against Klebsiella pneumoniae Infection In Vitro and In Vivo

“…Linezolid can impede the initiation of bacterial protein synthesis by binding to the 23S RNA peptidyl transferase of the 50S subunit in the bacterial ribosome ( Leach et al, 2007 ). Recently, combined with other antibiotics showed excellent synergistic and antibacterial activity against multidrug-resistant (MDR) pathogens infection ( Zhou et al, 2018 ; Zhuang et al, 2020 ), suggesting the potential of linezolid as candidate for developing novel combination therapeutic agents. However, combinations of linezolid and polymyxin derivatives for the treatment of KP infections remains an open question.…”