Bacterial Natural Product Drug Discovery for New Antibiotics: Strategies for Tackling the Problem of Antibiotic Resistance by Efficient Bioprospecting

Abstract

The problem of antibiotic resistance has become a challenge for our public health and society; it has allowed infectious diseases to re-emerge as a risk to human health. New antibiotics that are introduced to the market face the rise of resistant pathogens after a certain period of use. The relatively fast development of resistance against some antibiotics seems to be closely linked to their microbial origin and function in nature. Antibiotics in clinical use are merely products of microorganisms or derivatives of microbial products. The evolution of these antimicrobial compounds has progressed with the evolution of the respective resistance mechanisms in microbes for billions of years. Thus, antimicrobial resistance genes are present within the environment and can be taken up by pathogens through horizontal gene transfer. Natural products from bacteria are an important source of leads for drug development, and microbial natural products have contributed the most antibiotics in current clinical use. Bioprospecting for new antibiotics is a labor-intensive task as obstacles such as redetection of known compounds and low compound yields consume significant resources. The number of bacterial isolates one can theoretically investigate for new secondary metabolites is, on the other hand, immense. Therefore, the available capacity for biodiscovery should be focused on the most promising sources for chemical novelty and bioactivity, employing the appropriate scientific tools. This can be done by first looking into under- or unexplored environments for bacterial isolates and by focusing on the promising candidates to reduce the number of subjects.

Keywords: actinobacteria; antibiotic resistance; antibiotics; bioprospecting; biosynthetic potential; cyanobacteria; drug discovery; myxobacteria; natural products; secondary metabolites.

Figure 1

Structures of antibiotics with an anti-bacterial effect on Staphylococcus aureus/ MRSA: Penicillin G (1), methicillin (2), vancomycin, (3), oxacillin (4) and teixobactin (5).

Figure 2

Structure of colistin (6).

Figure 3

The dilemma of resistance against natural product-derived antibiotics. Antibiotic-producing bacteria exist in the same environments as antibiotic-resistant ones. Antibiotic resistance is also linked to antibiotic production by the respective producers’ resistance for “self-protection”. The resistance factors available within the environment finally contribute to the antimicrobial resistance (AMR) of clinically relevant pathogens.

Figure 4

Origin of small molecular drugs from Jan. 1981 to Sept. 2019. To the left, drugs over all indications are grouped, and to the right, specifically the anti-bacterial drugs are grouped for comparison. Numbers from Newman and Cragg [45]; the classifications from the original were pooled for simplification.