History of the streptothricin antibiotics and evidence for the neglect of the streptothricin resistome

Abstract

The streptothricin antibiotics were among the first antibiotics to be discovered from the environment and remain some of the most recovered antimicrobials in natural product screens. Increasing rates of antibiotic resistance and recognition that streptothricin antibiotics may play a role in countering so-called super-bugs has led to the re-evaluation of their clinical potential. Here we will review the current state of knowledge of streptothricins and their resistance in bacteria, with a focus on the potential for new resistance mechanisms and determinants to emerge in the context of potential widespread clinical adoption of this antibiotic class.

Fig. 1. Timeline of streptothricin advancements.

1942: initial discovery, 1946: detailed report of major toxicity during animal testing, 1952–1961: characterization of the main molecular components, 1972: complete structural description, 1978: mechanism of action described, 1982: first total synthesis completed, 1987: first genetic isolation of a streptothricin acetyltransferase (STAT), 1997: resistance-guided discovery of the biosynthetic gene cluster, 2006: first isolation of a streptothricin hydrolase (SttH), 2021: first genetic characterization of a putative streptothricin resistance rRNA methyltransferase, 2023: discovery of the precise molecular targets of streptothricins.

Fig. 2. Structures of streptothricin family antibiotics.

a General structure of the streptothricins (STC) highlighting the streptolidine lactam ring (blue), gulosamine sugar (black), and β-lysine residue(s) (red). Streptothricins are defined by the length of their β-lysine homopolymer chain, from one to seven residues. b Structural elements of the “streptothricin-like” antibiotics, highlighting variation in the streptolidine lactam ring (blue: methylation, hydroxylation, stereochemistry), the sugar (black: carbamoyl location), and the amino acid residue (red: N-methylation, presence of β-lysine or a glycine derivative). R-group features in bold signify the default substituent found in canonical streptothricins.

Fig. 3. Breakdown of antibiotic production in natural product culture collections.

Pie graph charting the prevalence of streptothricin (red), streptomycin (light green), macrolide or tetracycline (dark green), or other natural product (purple) production in an actinomycetes culture collection. Roughly 42% of actinomycetes were found to produce streptothricin. Figure based on data from ref. .

Fig. 4. Streptothricin resistance mechanisms compared to kanamycin.

a Biochemically confirmed streptothricin resistance mechanisms are limited to β-lysine acetylation and (potentially nonspecific) hydrolysis of the streptolidine lactam ring. b Kanamycin B resistance mechanisms include acetyl, phosphoryl, and nucleotidyltransferases targeting multiple sites, drug efflux, and 16 S ribosome subunit modification through methylation.

Fig. 5. Streptothricin acetyltransferase mechanism and diversity.

a Streptothricin acetyltransferase (Sat, STAT, or NAT) mechanism of action. Enzymatic transfer of an acetyl group from acetyl-CoA to the streptothricin amino group of β-lysine results in loss of antibiotic activity. b Phylogenetic tree of three novel predicted streptothricin acetyltransferases (“Soil NTC SatA/sta”, blue dots) captured by functional metagenomic selection in the context of CARD validated STAT, SatA, Sat-2, Sat-3, and Sat-4 enzymes, predicted streptothricin acetyltransferases, and other related acetyltransferases. b is modified from ref. (CC BY 4.0).

Fig. 6. Semi-synthetic antibiotics that resist modification.

a, b are natural product (left) and semi-synthetic (right) antibiotic pairs where modifications (red) have been introduced to combat antibiotic-modifying enzymes. a Sisomycin and plazomicin. b Chloramphenicol and florfenicol (replacement of the nitro group with a methyl-sulfonyl group, blue, is to combat toxicity, not resistance). c BD-12, a formimidoylglycyl-streptothricin and a hypothetical N-methylated streptothricin derivative could potentially avoid streptothricin acetyltransferase inactivation while maintaining activity.

Fig. 7. Streptothricin hydrolase mechanism.

Streptothricin hydrolase (SttH) catalyzes the opening of the streptolidine lactam ring resulting in an inactive streptothricin acid.

Fig. 8. Ribosome modifications conferring streptothricin resistance.

a E. coli 16 S rRNA representation showing approximate regions where mutations confer resistance to kanamycin (space filling, blue) or streptothricin (space filling, red). b Phylogenetic tree of ribosome methyltransferases from the comprehensive antibiotic resistance database (CARD) alongside a putative methyltransferase that confers resistance to streptothricin (soil_nt_13615, red). b is adapted from ref. (CC BY 4.0).