| Domagk-platform/In situ screening-platform |
Screening the efficacy of antimicrobial compounds at the site of infection (with the use of infection models; e.g., in an in situ mouse model or in a Caernorhabditis elegans worm model [47,48]) Detects prodrug compounds that would be missed by high-throughput screening and validation approaches [49] Ethical considerations (related to the use of animal models)
|
Sulfonamides (sulfamidochrysoidine) |
| Waksmann-platform/Natural products-platform |
Screening for secondary metabolites in soil microorganisms (Streptomycetes) with antibacterial activity [50] Main discovery platform in the golden era of antibiotic discovery [51] Background of known compounds during screening presents a major issue [45] Experiments are ongoing with the activation of “silent operons” in microorganisms [52] Focusing on uncultured microorganisms (representing 99% of total microbial diversity) and compound de-replication (using mass spectrometry and nuclear magnetic resonance (NMR)) are promising approaches [53] Screening for antibacterial compounds from plant and marine origins represents an untapped resource of potential drugs [54,55]
|
Penicillin (First antibiotic discovered)
Streptomycin (First drug active against tuberculosis (TB))
Daptomycin (MDR Gram-positives)
Fidaxomicin (Clostridioides difficile) |
| Species-selective platform |
Screening against a specific bug, resulting in compounds that act selectively against that pathogen [56] Requires a target that is innate and specific to microorganism Lower probability of toxicity in the human host New compounds will not affect commensals in the gut [57]
|
Bedaquiline F1F0-ATPase-inhibitor in Mycobacterium tuberculosis complex
Ethambutol Arabinosyl-transferase-inhibitor in Mycobacterium tuberculosis complex
|
High-throughput screening (HTS)
Combinatorial chemistry (CC)
Rational drug design (RDD) |
|
Oxazolidinones Inhibitors of protein synthesis by interfering with the ribosomal 50S subunit |
| Antimicrobial peptides (AMPs) |
Use of small-sized, positively charged, amphipathic molecules synthesized by plants, animals or other bacteria [59] They play an important role in innate immunity in humans (e.g., defensins) [60] Structurally, they may be α-helices, β-sheets or extended coils, all with different mechanisms of action [61] Toxicity in humans in higher concentrations [61] Difficulties in formulation [62]
|
No AMP has been approved yet for clinical use |
| Resistance reversing compounds |
Compounds affecting a defined mechanism of bacterial resistance, e.g., antibiotic-degrading enzymes, efflux pumps [3] Strains that are resistant to specific antibiotics may be sensitized, maintaining the efficacy of current drug pool [63,64,65] The clinical relevance of efflux pump inhibitors (EPIs) is hard to determine
|
Beta-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam, avibactam etc.)
No EPI has been approved yet for clinical use |
| Virulence modulation |
Compounds targeting expression and/or activity of bacterial virulence factors (capsule, toxins, fimbriae, biofilm) essential in their pathogenesis [66,67] Various small-molecule compounds (e.g., quorum sensing-inhibitors) and monoclonal antibodies have been described [68,69] Selective pressure to develop resistance is not present [68] The clinical relevance of virulence modulators is hard to determine
|
No virulence modulator has been approved yet for clinical use |
