Macrocycle-Antibiotic Hybrids: A Path to Clinical Candidates

Abstract

The tale of abate in antibiotics continued defense mechanisms that chaperone the rise of drug-defying superbugs—on the other hand, the astray in antibacterial drug discovery and development. Our salvation lies in circumventing the genesis of resistance. Considering the competitive advantages of antibacterial chemotherapeutic agents equipped with multiple warheads against resistance, the development of hybrids has rejuvenated. The adoption of antibiotic hybrid paradigm to macrocycles has advanced novel chemical entities to clinical trials. The multi-targeted TD-1792, for instance, retained potent antibacterial activities against multiple strains that are resistant to its constituent, vancomycin. Moreover, the antibiotic conjugation of rifamycins has provided hybrid clinical candidates with desirable efficacy and safety profiles. In 2020, the U.S. FDA has granted an orphan drug designation to TNP-2092, a conjugate of rifamycin and fluoroquinolone, for the treatment of prosthetic joint infections. DSTA4637S is a pioneer antibacterial agent under clinical development and represents a novel class of bacterial therapy, that is, antibody–antibiotic conjugates. DSTA4637S is effective against the notorious persistent S. aureus bacteremia, a revelation of the abracadabra potential of antibiotic hybrid approaches.

Recent Advances in Macrocyclic Drugs and Microwave-Assisted and/or Solid-Supported Synthesis of Macrocycles

“…In this context, such other recently approved macrocyclic oral drugs with minimal absorption include antibacterial Aemcolo (rifamycin SV) for managing and treating travelers’ diarrhea and Dificid (fidaxomicin) for the treatment of adult patients with C. difficile infections [ 13 ]. In addition, several advanced macrocycle clinical candidates were developed using the macrocycle–antibiotic hybrid strategy [ 5 ].…”

“…Macrocycles continue to serve as an important class of compounds and have had a profound impact on chemistry, biology, and medicine [ 1 , 2 , 3 ]. Because of their cyclic nature, conformational and configurational characteristics, along with template-induced preorganization associated with macrocycles [ 4 ], compared to small molecule drugs and large biologics, macrocycles can offer unique drug-like profiles such as favorable pharmacokinetic and pharmacodynamic (PK/PD) parameters and improved oral bioavailability, enhanced metabolic stability and cell permeability, increased binding affinity, and desirable conformational rigidity [ 1 , 5 ]. As such, new synthetic strategies and structure–activity relationship (SAR) studies of macrocyclic chemical entities and related natural products remain an attractive research area in this field [ 6 , 7 , 8 ].…”

Beyond the approved: target sites and inhibitors of bacterial RNA polymerase from bacteria and fungi

“…256 In January 2020, the FDA has granted an orphan drug designation to TNP-2092 (TenNor Therapeutics) for the treatment of prosthetic joint infections. 257 3.1.2. Kanglemycins.…”

Combating Antibiotic Resistance in Bacteria: The Development of Novel Therapeutic Strategies

“…Infections of the joints Antibody-antibiotic conjugates are a unique type of bacterial treatment. 132…”