The Concept of an Ideal Antibiotic: Implications for Drug Design

Abstract

The emergence and spread of antibiotic-resistant pathogens is a major public health issue, which requires global action of an intersectoral nature. Multidrug-resistant (MDR) pathogens-especially "ESKAPE" bacteria-can withstand lethal doses of antibiotics with various chemical structures and mechanisms of action. Pharmaceutical companies are increasingly turning away from participating in the development of new antibiotics, due to the regulatory environment and the financial risks. There is an urgent need for innovation in antibiotic research, as classical discovery platforms (e.g., mining soil Streptomycetes) are no longer viable options. In addition to discovery platforms, a concept of an ideal antibiotic should be postulated, to act as a blueprint for future drugs, and to aid researchers, pharmaceutical companies, and relevant stakeholders in selecting lead compounds. Based on 150 references, the aim of this review is to summarize current advances regarding the challenges of antibiotic drug discovery and the specific attributes of an ideal antibacterial drug (a prodrug or generally reactive compound with no specific target, broad-spectrum antibacterial activity, adequate penetration through the Gram-negative cell wall, activity in biofilms and in hard-to-treat infections, accumulation in macrophages, availability for oral administration, and for use in sensitive patient groups).

Keywords: ESKAPE; Mycobacterium; antibiotic; biofilm; drug discovery; metronidazole; multidrug-resistance; persisters; prodrug.

Figure 1

Antibiotics that closely resemble the properties set up by the ideal antibiotic (prodrug) model. (A): metronidazole; (B) ethionamide (ETH); (C) isoniazid (INH); D: pyrazinamide (PYR).