Challenges of antibacterial discovery revisited

Abstract

The discovery of novel antibiotic classes has not kept pace with the growing threat of bacterial resistance. Antibiotic candidates that act at new targets or via distinct mechanisms have the greatest potential to overcome resistance; however, novel approaches are also associated with higher attrition and longer timelines. This uncertainty has contributed to the withdrawal from antibiotic programs by many pharmaceutical companies. Genomic approaches have not yielded satisfactory results, in part due to nascent knowledge about unprecedented molecular targets, the challenge of achieving antibacterial activity by lead optimization of enzyme inhibitors, and the limitations of compound screening libraries for antibacterial discovery. Enhanced diversity of compound screening banks, entry into new chemical space, and new screening technologies are currently being exploited to improve hit rates for antibacterial discovery. Antibacterial compound lead optimization faces hurdles associated with the high plasma exposures required for efficacy. Lead optimization would be enhanced by the identification of new antibiotic classes with improved tractability and by expanding the predictability of in vitro safety assays. Implementing multiple screening and target identification strategies is recommended for improving the likelihood of discovering new antibacterial compounds that address unmet needs.

The re-emergence of natural products for drug discovery in the genomics era

“…Genes that are specific to bacteria were deleted to determine which genes were essential for bacterial viability 201 and to identify antibacterial targets. However, such efforts have not yielded the success that was anticipated [201][202][203] and no new drugs emerged [204][205][206] . A G " K mpaigns revealed that 67 HTS campaigns against targets that were selected from a panel of 160 genes that had been predicted to be essential for microbial viability failed to generate candidates for clinical development 203 .…”

“…Perhaps the promise that was offered by genomic approaches took attention from the fact that successful development of antibacterial drugs is always particularly challenging 202,204,206 .…”

“…Second, the challenges of moving from hits in a molecular screen to a compound that could reach its intracellular target at an effective concentration were underestimated. Third, the chemical libraries that were used for screening were not sufficiently biologically relevant 202,[204][205][206] . Moreover, it has also been argued that a focus on genomically predicted targets that are single enzymes means that any compounds that are found to be active are liable to trigger drug-resistance mechanisms 204 .…”

Untitled

“…Halen de kullanmakta olduğumuz bu ajanlar, bakterilerin bellibaşlı fizyolojik süreçleri üzerinde etkili olurlar. Bunlar, hücre duvarı biyosentezi (β-laktamlar, glikopeptidler), hücre zarı (lipopeptidler, polimiksinler), tip II topoizomerazlar (florokinolonlar), ribozomlar (makrolidler, aminoglikozidler, tetrasiklinler, glisilsiklinler, oksazolidinonlar, streptograminler), transkripsiyon (rifampisin) ve folat biyosentezi (sülfonamidler ve trimetoprim) olarak sıralanabilir (2).…”

Optimizing Antibiotic Pharmacodynamics for Clinical Practice

“…Given current trends in infectious disease, it's unfortunate that the scientific, regulatory, and economic challenges of antibiotic research have led to a decline in the approval of new agents [4,5,[8][9][10][11][12][13]. Today, there are few new antibiotics in late stage development offering activity against the most dangerous hospital acquired gram-negative pathogens [14][15][16].…”