Abstract
In the fight against antimicrobial resistance (AMR), antibiotic biosynthetic gene clusters are constantly being discovered. These clusters often include genes for membrane transporters that are involved in the export of the produced natural product during biosynthesis and/or subsequent resistance through active efflux. Despite transporter genes being integral parts of these clusters, study of the function of antibiotic export in natural producers such as Streptomyces spp. remains underexplored, in many cases lagging far behind our understanding of the biosynthetic enzymes. More efficient release of antibiotics by producing cells has potential benefits to industrial biotechnology and understanding the relationships between exporters in natural producers and resistance-associated efflux pumps in pathogens can inform our efforts to understand how AMR spreads. Herein we compile and critically assess the literature on the identification and characterization of antibiotic exporters and their contribution to production in natural antibiotic producers. We evaluate examples of how this knowledge could be used in biotechnology to increase yields of the final product or modulate its chemical nature. Finally, we consider the evidence that natural exporters form a reservoir of protein functions that could be hijacked by pathogens as efflux pumps and emphasize the need for much greater understanding of these exporters to fully exploit their potential for applications around human health.
Highlights
Antimicrobial resistance (AMR) is one of the most urgent global challenges to human health [1, 2]
The vast majority of biosynthetic gene clusters (BGCs)-linked antibiotic exporters belongs to various subgroups of the ATP-binding cassette (ABC) superfamily and major facilitator superfamily (MFS) of transporters (Fig. 1, Table 1), which while differing by structure, transport mechanism, and mode of energization (Fig. 1) [17, 18], collectively account for much of efflux-related MDR in nature [19]
While it is commonly assumed that BGC-linked exporters function in the secretion of the antibiotic made by the BGC, the exact nature and importance of their physiological role have been relatively poorly studied and very rarely exploited in biotechnological approaches to improve antibiotic production
Summary
Antimicrobial resistance (AMR) is one of the most urgent global challenges to human health [1, 2]. The scarcity of effective antimicrobials against multidrug-resistant (MDR) pathogens has led the mainstream media to warn of an ‘antibiotic apocalypse’ [3], and has compelled the scientific community to direct considerable effort at the discovery of novel molecules able to combat such organisms [4,5,6,7]. Novel biosynthetic gene clusters (BGCs) for antibiotics are being reported in ever-growing numbers from genome and environmental DNA sequencing projects. BGCs often contain genes for exporters [15, 16], integral membrane proteins responsible for the secretion of an enormous variety of molecules including antibiotics (Fig. 1). Most studies that discover and manipulate BGCs involved strategies that only focus on the biosynthetic genes [20] and do not consider manipulating export as an option
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