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Streptogramin

Streptogramins are a class of antibiotics produced by certain species, characterized by their structure and ability to inhibit bacterial protein through synergistic action of two distinct chemical groups. Group A streptogramins are polyunsaturated macrolactones derived from , while group B streptogramins are formed via , typically produced in a 70:30 ratio by the producing . This combination renders them particularly effective against , including multidrug-resistant strains, by binding to the 50S ribosomal subunit and disrupting translation, often achieving bactericidal effects where individual components are merely bacteriostatic. The mechanism of action centers on the peptidyl transferase center (PTC) of the bacterial , where molecules bind first, stimulating the dissociation of peptidyl-tRNA from the and potentially interfering with nascent polypeptide release. molecules subsequently bind, preventing accommodation at the A-site and inhibiting formation, thereby halting polypeptide chain elongation. This sequential binding induces a ribosomal conformational change that enhances affinity by up to 100-fold, explaining the observed , which remains robust even against ribosomes modified by or lincosamide resistance. Discovered during the mid-20th-century boom, the first streptogramin, virginiamycin, was isolated in 1952 from virginiae and initially used as a growth promoter in . Pristinamycin, another natural mixture, was identified in 1958 from Streptomyces pristinaespiralis and approved for human use in in 1975 for treating skin and respiratory infections caused by Gram-positive cocci. Semisynthetic derivatives, such as quinupristin (group B) and dalfopristin (group A), were developed to improve solubility and , leading to the fixed-ratio combination (Synercid). In clinical practice, streptogramins serve as agents of last resort for severe due to vancomycin-resistant Enterococcus faecium (VRE), methicillin-resistant Staphylococcus aureus (MRSA), and other resistant Gram-positive pathogens. Synercid received accelerated FDA approval in 1999 for treating complicated skin and skin structure (at 7.5 mg/kg intravenously every 12 hours) and VRE bacteremia (at 7.5 mg/kg intravenously every 8 hours) in adults. Pristinamycin remains available orally in for outpatient of staphylococcal and streptococcal , though resistance mechanisms—such as efflux pumps, enzymatic inactivation, and ribosomal mutations—pose ongoing challenges to their efficacy.

Overview

Definition and classification

Streptogramins are a class of antibiotics that inhibit bacterial protein synthesis by binding to the center (PTC) on the 50S subunit of the bacterial . They comprise a family of structurally related cyclic peptides produced as secondary metabolites by species of the bacterium , such as Streptomyces pristinaespiralis. The name "streptogramin" originates from their production by Streptomyces species, highlighting their natural bacterial derivation. Streptogramins are classified into two principal groups based on distinct chemical architectures: Group A streptogramins, consisting of polyunsaturated macrolactones, and Group B streptogramins, comprising cyclic hexadepsipeptides. These groups are biosynthesized by Streptomyces in a natural ratio of approximately 7:3 (Group A to Group B), which is often maintained in pharmaceutical formulations to optimize activity. As a subclass of inhibitors, streptogramins target the same ribosomal PTC as but differ in their molecular structures and exhibit generally bacteriostatic effects when administered individually. This classification underscores their role as a unique family, separate from macrolides despite the shared binding site.

Clinical significance

Streptogramins, particularly the combination quinupristin/dalfopristin (Synercid), serve as drugs of last resort for treating multidrug-resistant Gram-positive infections, including those caused by vancomycin-resistant Enterococcus faecium (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). Their bactericidal activity targets the 50S ribosomal subunit, providing efficacy against isolates resistant to beta-lactams and glycopeptides, where options like vancomycin fail. In clinical guidelines, they are recommended as salvage therapy for persistent MRSA bacteremia or VRE infections when first-line agents are ineffective. The emergence of streptogramins in occurred in the 1990s amid escalating resistance to beta-lactams and glycopeptides among Gram-positive pathogens. received FDA approval in 1999 specifically for serious VRE infections, addressing the urgent need for alternatives as VRE cases surged in hospitals. This development was driven by the global rise in MRSA and VRE, which compromised standard therapies and highlighted the need for novel classes like streptogramins. As of 2025, streptogramins maintain limited but critical relevance in settings for managing resistant Gram-positive infections, such as complicated and infections, bacteremia, and . Their use is reserved for cases involving VRE or MRSA with reduced susceptibility to or , often in combination regimens to enhance outcomes in severe scenarios like . Post-2000 surveillance data indicate sustained efficacy against vancomycin-resistant S. aureus (VRSA), a rare but high-risk , with streptogramins retaining susceptibility in reported isolates due to their distinct mechanism unaffected by vanA-mediated glycopeptide resistance. Global usage trends show streptogramins are more prevalent in than human applications, with virginiamycin widely employed in animal for growth promotion and disease prevention in and . This disparity raises concerns about cross-resistance, as veterinary exposure has contributed to the spread of resistance genes like vat and vga, potentially impacting human streptogramin efficacy, though human clinical resistance remains low in surveillance programs.

Chemical structure

Group A streptogramins

Group A streptogramins are characterized by a core structure consisting of a 23-membered polyunsaturated macrolactone ring featuring conjugated double bonds and an oxazole ring, which provides structural rigidity essential for interaction with the bacterial ribosome. This macrocyclic framework incorporates peptide bonds and a dienylamide fragment, distinguishing it from other ribosomal inhibitors. A representative natural example is pristinamycin IIA, produced by pristinaespiralis, while dalfopristin serves as a key semisynthetic derivative modified for improved stability. Dalfopristin has the molecular formula C<sub>34</sub>H<sub>50</sub>N<sub>4</sub>O<sub>9</sub>S and a molecular weight of 690.85 Da. These compounds exhibit lipophilic properties due to their extensive unsaturated ring system, resulting in poor aqueous that poses significant challenges for and necessitates specialized intravenous delivery methods such as reconstitution in dextrose solutions. Structurally, streptogramins induce a conformational shift in the ribosomal center upon binding, as revealed by crystallographic studies showing alterations in key 23S rRNA residues without detailing the functional implications.

streptogramins

streptogramins are defined by their depsipeptide architecture, consisting of cyclic hexa- or heptadepsipeptides in which are linked through alternating and (depsi) bonds to form a macrocyclic structure. These molecules typically feature a 19-membered macrocyclic ring that incorporates a central functionality. Key structural elements include the incorporation of specific such as L-proline and pipecolic acid (or its 4-oxo derivative in some variants), along with residues like L-threonine, D-aminobutyric acid, and phenylglycine. A prominent natural representative is pristinamycin IA, produced by pristinaespiralis, which serves as the core scaffold for this group. Quinupristin, a semisynthetic of pristinamycin IA, is widely used in clinical settings and has the molecular formula C_{53}H_{67}N_{9}O_{10}S. This modification introduces a 4-(dimethylamino)-N-methyl-L-phenylalanine residue, which enhances in aqueous formulations compared to the parent natural . Like other natural streptogramins, Group B members exhibit limited , often requiring semisynthetic alterations or combination with Group A components for pharmaceutical stability and intravenous administration.

Mechanism of action

Individual binding and inhibition

Streptogramins target the 50S subunit of the bacterial 70S , specifically at the center (PTC), where they exert their inhibitory effects on protein synthesis. Group A streptogramins, such as dalfopristin, primarily at the entrance to the A-site tunnel within the PTC, spanning the A-site cleft and partially encroaching into the . This positioning allows them to interact with key 23S rRNA , including A2062 and U2585, through hydrogen bonding and hydrophobic van der Waals interactions that stabilize their . In contrast, group B streptogramins, such as quinupristin, to the region adjacent to the PTC, within the nascent peptide exit tunnel (NPET), forming hydrogen bonds with residues like A2062 and C2586, alongside van der Waals contacts with rRNA domains II, IV, and V. These distinct yet overlapping sites ensure selective affinity for bacterial ribosomes, as eukaryotic 60S subunits lack the corresponding rRNA sequences (e.g., bacterial-specific A2062) and structural features, resulting in no significant or inhibition in eukaryotic systems. Individually, group A streptogramins inhibit protein synthesis by distorting the PTC conformation, which mispositions the CCA-ends of A- and tRNAs and prevents proper formation. This interference primarily affects the initiation and early elongation stages, leading to a bacteriostatic effect by halting without causing . For instance, binding induces a wobble base-pair between U2506 and G2583 in 23S rRNA, rendering the PTC catalytically inactive and blocking accommodation at the A-site. streptogramins, acting alone, stimulate the of peptidyl-tRNA from the and obstruct the passage of the nascent chain through the NPET, thereby inhibiting elongation and also producing a bacteriostatic outcome. Their binding competes directly with antibiotics for the same exit tunnel site near the PTC, but group A streptogramins occupy a distinct position closer to the nascent peptide exit tunnel entrance, avoiding overlap with macrolide binding and allowing activity against some macrolide-resistant strains. These individual mechanisms highlight the partial inhibitory potential of each group, relying on precise molecular interactions that exploit bacterial architecture for selectivity and efficacy.

Synergistic effects

The synergistic effects of streptogramins stem from the of Group A and Group B components to overlapping sites within the center (PTC) of the bacterial 50S ribosomal subunit. Binding of a Group A streptogramin first induces a conformational change in the , particularly involving like A2062 and U2585 in the 23S rRNA, which allosterically enhances the binding affinity for the subsequent Group B component by 10- to 100-fold. This increased affinity arises from the stabilization of a distorted PTC that favors Group B docking, as demonstrated in biochemical binding assays and structural analyses. In combination, the two groups lock the in an irreversible "frozen" state, trapping peptidyl-tRNA in the while blocking accommodation in the A site and inhibiting formation. This cooperative inhibition also prevents the binding of elongation factors EF-Tu and , halting translocation and nascent chain . Cryo-EM structures of streptogramin-bound ribosomes confirm this stabilized, non-productive conformation, with key interactions such as hydrogen bonding between the antibiotics and rRNA bases maintaining the even after individual component dissociation. The result is a profound shift from the bacteriostatic effects of either group alone to bactericidal activity of the pair, driven by the irreversible inhibition of and a 100-fold increase in overall potency against susceptible . This remains effective regardless of bacterial efflux pumps, as both components are similarly susceptible to , but it is highly sensitive to conferred by modifying enzymes, such as Vat acetyltransferases that target streptogramins and disrupt the initial conformational trigger.

Medical uses

Indications and spectrum

Streptogramins, particularly the combination (Synercid), exhibit a narrow spectrum of activity primarily targeting Gram-positive aerobic bacteria, including staphylococci, streptococci, and certain enterococci. They demonstrate strong in vitro activity against methicillin-susceptible and , coagulase-negative staphylococci, *, *, and vancomycin-resistant * (VRE), with minimum inhibitory concentrations (MICs) typically ≤1 μg/mL indicating susceptibility. Activity is absent against Enterococcus faecalis due to intrinsic resistance, limiting utility against this species. Against anaerobes, efficacy is variable but includes good coverage of Gram-positive species such as * spp. and * spp., while activity against Gram-negative anaerobes like * is inconsistent and generally weaker. Gram-negative aerobes, including and * spp., show poor susceptibility, with MICs often exceeding 4 μg/mL, rendering streptogramins ineffective for these pathogens. The U.S. Food and Drug Administration (FDA) initially approved quinupristin/dalfopristin in September 1999 for treating serious or life-threatening infections associated with VRE faecium bacteremia and complicated skin and skin structure infections caused by methicillin-susceptible S. aureus or S. pyogenes, but the VRE indication was removed from labeling in 2010 due to insufficient confirmatory evidence of clinical benefit. Prior to its discontinuation, off-label use extended to resistant cases of nosocomial pneumonia due to Gram-positive pathogens, where clinical trials had shown efficacy comparable to vancomycin, achieving clinical success rates of approximately 50-60% in ventilator-associated pneumonia. As of 2025, (Synercid) is no longer available following its discontinuation in 2022. Pristinamycin remains available orally in for outpatient of staphylococcal and streptococcal infections. Efficacy data underscore streptogramins' targeted role in resistant Gram-positive infections, with an MIC<sub>90</sub> of 1 μg/mL against VRE faecium isolates, supporting >90% in clinical collections. This potency is less pronounced against E. faecalis, where resistance rates approach 100%, highlighting the need for species-specific testing. In the context of post-2020 challenges, such as increased multidrug-resistant superinfections in patients, streptogramins were considered for VRE co-infections prior to the discontinuation of Synercid, though specific outcome data remain limited amid broader efforts to curb resistance surges.

Administration and formulations

Streptogramins for human use were primarily administered intravenously due to limited oral , with (marketed as Synercid) having been the main formulation approved until its discontinuation in 2022. This combination antibiotic consisted of a fixed 30:70 ratio of quinupristin to dalfopristin, designed to replicate the natural synergistic interaction between and streptogramins for enhanced antibacterial efficacy. Synercid was supplied as a powder for injection in 500 mg vials (150 mg quinupristin and 350 mg dalfopristin per vial) and had to be reconstituted with sterile , then further diluted in 5% dextrose in for intravenous over 60 minutes to minimize venous irritation. It was incompatible with saline solutions, and flushing the intravenous line with saline or after administration was not recommended to avoid precipitation. The standard adult dosage of Synercid was 7.5 mg/kg (of total drug) administered every 12 hours for complicated skin and skin structure infections, with treatment durations typically ranging from 7 to 14 days depending on the infection site. For pediatric patients, dosing had been evaluated in limited emergency-use settings at 7.5 mg/kg every 8 or 12 hours, though and data remained incomplete, necessitating careful monitoring and no routine adjustments for or renal impairment since the drug was not significantly cleared by . Infusion-related challenges included the requirement for dextrose-based diluents and potential venous tolerability issues, which could be mitigated by slowing the infusion rate if needed. In , pristinamycin—a natural streptogramin complex similar to virginiamycin—is available as an oral formulation (Pyostacine) for treating staphylococcal and streptococcal infections, offering an alternative to where appropriate. It is dosed at 2 to 4 g per day in divided doses (e.g., 1 g two to three times daily) for adults, with tablets of 250 mg or 500 mg strengths, and is generally well-tolerated at these levels for 7 to 10 days. Pristinamycin's oral route leverages its better gastrointestinal absorption compared to synthetic combinations like Synercid, though it is not approved . Virginiamycin, another natural streptogramin, is restricted to veterinary applications as an oral feed additive to promote growth and improve feed efficiency in such as and , with no formulations or approvals for human administration due to and concerns. Typical veterinary dosing involves incorporation into at 5 to 20 g per , but human exposure is limited to potential residues, which regulatory assessments deem low risk.

Pharmacology

Pharmacokinetics

Streptogramins, particularly the combination product administered intravenously in a 30:70 , exhibit negligible oral and are primarily given by due to poor gastrointestinal uptake. In contrast, the natural streptogramin pristinamycin, used orally in regions outside the , demonstrates limited of approximately 15-20% following oral dosing, attributed to first-pass and variable . Intravenous administration of results in rapid distribution, with steady-state volumes of distribution of 0.45 L/kg for quinupristin and 0.24 L/kg for dalfopristin. Quinupristin and dalfopristin display high , ranging from 55-78% for quinupristin and 11-26% for dalfopristin, which influences their tissue distribution profile. The drugs achieve good penetration into and tissues, with concentrations in blister fluid reaching about 19% and 11% of levels for the parent compounds, respectively, though total levels including metabolites approach 40% of concentrations. Penetration into is poor, limiting utility in infections. Metabolism of occurs primarily in the liver through nonenzymatic processes, including of dalfopristin to the pristinamycin IIA and conjugation of quinupristin to active and derivatives, which retain antibacterial activity comparable to the parent compounds. Although not metabolized by enzymes, inhibits , potentially affecting co-administered drugs. Elimination is predominantly via biliary and fecal routes, accounting for 75-77% of the dose, with urinary excretion contributing 15-19%. The elimination half-lives are approximately 0.85 hours for quinupristin and 0.70 hours for dalfopristin, while active metabolites exhibit slightly longer half-lives of 1.2-1.8 hours. In hepatic impairment, area under the curve increases significantly (up to 180% for quinupristin in Child-Pugh A/B patients), necessitating dose adjustments, whereas renal impairment has minimal impact and no adjustment is required.

Adverse effects and contraindications

Streptogramins, particularly the combination (Synercid), are associated with a range of adverse effects, primarily related to infusion site reactions and musculoskeletal symptoms. Infusion-related effects are common, including pain at the infusion site in approximately 40% of patients and or in up to 42%, often necessitating central venous access for prolonged therapy. Other frequent toxicities include hyperbilirubinemia, occurring in about 25% of patients with total bilirubin elevations exceeding five times the upper limit of normal, and arthralgias or myalgias in 5-10% of cases, which can be severe and reversible upon discontinuation. Serious risks are less common but include cholestatic hepatitis, which presents with a cholestatic pattern of in rare instances, potentially leading to and requiring prompt cessation of therapy. or anaphylactoid reactions occur infrequently, affecting less than 0.1% of patients. inhibits , potentially increasing levels of co-administered substrates like cyclosporine, with reported increases in area under the curve by up to 63%. Contraindications include known to streptogramins or their components. Use with caution in patients with severe , as hepatic impairment can elevate blood levels and exacerbate toxicities; caution is advised in those with pre-existing due to the risk of worsening hyperbilirubinemia. Monitoring is essential, particularly for liver function, with regular assessment of liver enzymes and levels recommended to detect hyperbilirubinemia or emerging early. Post-marketing data indicate low rates of treatment failures linked to but a high discontinuation rate of approximately 25% due to adverse effects, underscoring the need for close clinical .

History

Discovery and natural sources

Streptogramins, a class of s, were first identified in the mid-20th century through microbial screening efforts focused on soil actinomycetes. In 1952, Belgian researchers Paul De Somer and Paul Van Dijck at the University of Leuven isolated virginiamycin, initially termed antibiotic 899 or staphylomycin, from the fermentation broth of virginiae, with a preliminary report published in 1955. This discovery stemmed from systematic searches for novel antibacterials effective against Gram-positive pathogens, revealing virginiamycin's potent activity against staphylococci and streptococci. The compound was characterized as a mixture of two synergistic components, factors M (a depsipeptide) and S (a macrocyclic ), which together inhibit bacterial protein synthesis. Building on this, in 1958, French scientists including Henri Preud'homme and colleagues at laboratories isolated pristinamycin from pristinaespiralis, marking another milestone in streptogramin discovery. Pristinamycin, also known as 7293 RP, was identified through similar soil-derived microbial cultures and patented in 1961 for its broad-spectrum activity against , including those resistant to other antibiotics of the era. Like virginiamycin, it comprises two complementary factors (PI and PII) that exhibit enhanced efficacy in combination. These early isolations highlighted the potential of actinomycetes as prolific sources of structurally diverse antibiotics. Naturally occurring streptogramins are primarily produced by various Streptomyces species, with S. virginiae serving as the key producer of virginiamycin factors M and S in soil environments. Other species, such as S. pristinaespiralis, yield related analogs like pristinamycin, underscoring the genus's role in generating these polyketide-peptide hybrids as secondary metabolites for ecological competition. Since the , virginiamycin has been widely incorporated as a feed additive in veterinary , particularly for and , to promote growth and improve feed efficiency by modulating and reducing subclinical infections. This application has helped minimize the reliance on therapeutic antibiotics in production, though it has raised concerns about long-term ecological impacts.

Development of therapeutic agents

The development of streptogramin therapeutic agents involved semisynthetic modifications to natural precursors, such as pristinamycin isolated from species, to enhance and suitability for clinical use. In the , researchers at Rhone-Poulenc Rorer engineered quinupristin and dalfopristin through from pristinamycin components, yielding water-soluble derivatives that retained potent antibacterial activity while addressing the poor aqueous of the parent compounds. These modifications enabled intravenous , marking a key advancement over earlier oral-only options. Phase III clinical trials in the evaluated the 30:70 combination of (marketed as Synercid) specifically for (VRE) infections, demonstrating clinical success rates of approximately 60-70% in treating serious VRE bacteremia and other invasive infections. Synercid received U.S. approval on September 21, 1999, for the treatment of complicated skin and skin structure infections caused by or , as well as serious or life-threatening infections associated with VRE. In , pristinamycin—an oral mixture of natural streptogramin A and B components—had been approved earlier, with initial market launch in 1973 for Gram-positive bacterial infections, providing an outpatient treatment option unavailable with the intravenous Synercid. Major challenges in streptogramin development centered on optimizing for parenteral delivery and mitigating profiles, including frequent (up to 40% incidence in trials) and /. Efforts to create viable oral formulations encountered setbacks; for instance, XRP 2868, a semisynthetic oral streptogramin combination developed by Aventis in the early 2000s, showed promising activity against resistant Gram-positive pathogens but failed to advance beyond phase II due to pharmacokinetic limitations and was ultimately discontinued. Investigational approaches have explored streptogramin combinations with beta-lactams to expand activity against multidrug-resistant Gram-positive and select , building on observed synergies. Additionally, the Union's 2006 ban on streptogramins like virginiamycin as animal growth promoters has influenced supply chains for the antibiotic class, contributing to shifts in production priorities and potential constraints on raw material availability for human therapeutics.

Biosynthesis

Producing organisms

Streptogramins are primarily synthesized by species within the genus Streptomyces, a group of soil-dwelling, Gram-positive actinobacteria belonging to the phylum Actinobacteria. The key producing organisms include Streptomyces pristinaespiralis, which generates the pristinamycin complex, and Streptomyces virginiae, responsible for virginiamycin production, with additional related actinomycetes contributing to the diversity of these antibiotics. These bacteria thrive in terrestrial soil ecosystems, where they form filamentous mycelia and produce streptogramins as secondary metabolites during their stationary growth phase. This production serves an ecological role by inhibiting the growth of competing bacteria and fungi, thereby facilitating nutrient acquisition and niche establishment in nutrient-limited environments. Actinobacteria, including Streptomyces species that produce streptogramins, are ubiquitous in soil with densities up to 10^7 colony-forming units per gram, underscoring their prominence in microbial communities. Over 20 distinct natural streptogramins have been identified across various Streptomyces strains, reflecting structural variations in their A and B components. For industrial applications, high-yield mutant strains have been developed; for instance, optimized S. virginiae VKM Ac-2738D achieves virginiamycin titers of up to 5.6 g/L in fed-batch fermentation processes. A distinctive feature of these producers is their bimodal , which maintains an optimal of streptogramin A to B components—approximately 30:70 for pristinamycin—to ensure synergistic antibacterial efficacy. These organisms are generally non-pathogenic to humans, with infections being exceedingly rare.

Biosynthetic pathways

Streptogramins are produced through distinct biosynthetic pathways involving non-ribosomal peptide synthetases (NRPS) for group B components and hybrid (PKS)/NRPS systems for group A components. These pathways assemble complex structures from specialized precursors, with the genetic machinery organized into large clusters that coordinate precursor supply, chain elongation, and tailoring reactions. The of streptogramins, such as pristinamycin I and virginiamycin S, proceeds via modular NRPS enzymes that construct a cyclic hexadepsipeptide backbone. These NRPS systems incorporate six building blocks, including atypical like L-phenylglycine, 4-oxo-L-pipecolic acid, and 3,3-dimethyl-3-aminopropanoic acid (DMAPA), alongside standard residues such as L-threonine, L-proline, and L-2-aminobutyric acid. The assembly involves sequential activation, , and thioesterification by adenylation (A), (C), and peptidyl carrier protein () domains, with additional methyltransferase (MT) domains for side-chain modifications and a thioesterase () for cyclization via an ester bond, forming the depsipeptide ring. Key NRPS enzymes include SnbA, SnbC, and SnbDE in pristinamycin I production, where atypical activations handle modified substrates like 3-hydroxypicolinic acid derived from L-proline. Precursor supply genes, such as pglA-E for L-phenylglycine and snbF for pipecolic acid derivatives, flank the core NRPS modules to ensure availability of non-canonical monomers. Group A streptogramins, exemplified by pristinamycin and virginiamycin , are synthesized by PKS/NRPS megaenzymes that build a polyunsaturated 23-membered macrolactone ring. The pathway initiates with an isobutyryl-CoA starter unit extended by six malonyl-CoA-derived ketide units and incorporates three (L-proline, L-serine, ) via NRPS modules, resulting in a polyketide-peptide . The comprises eight iterative PKS modules for β-keto (ketoreduction, , enoyl ) and two NRPS modules for formation, organized across multidomain proteins like VirA, VirF, VirG, and VirH in virginiamycin M biosynthesis, totaling 24 PKS domains and seven NRPS domains. In pristinamycin II, the SnaE1-E4 complex handles loading, ketide extension, and amino acid integration, with a discrete acyltransferase () for malonyl transfer and an HMG-CoA cassette (SnaG-K) introducing a C-14 methyl branch via 3-hydroxy-3-methylglutaryl (HMG) activation. Recent studies (as of ) have decrypted the programming of β-methylation in virginiamycin M, revealing details of PKS module specificity for branched chain incorporation. These modules ensure the characteristic conjugated and ring in the macrolactone core. The genetic basis for streptogramin production resides in large biosynthetic gene clusters spanning 62-120 kb, such as the 62 kb virginiamycin M cluster in virginiae or the ~120 kb pristinamycin-specific portion of the 210 kb supercluster in S. (e.g., and loci). These clusters encode not only the core synthetases but also accessory genes for precursor and resistance. is mediated by pathway-specific activators, including antibiotic regulatory proteins (SARPs) like PapR1-5 and TetR-family repressors (e.g., PapR2), which respond to nutritional cues to induce transcription, often in a Streptomyces pristinaespiralis binding (SpbR)-dependent manner. Global regulators like SpbR integrate cluster activation with cellular metabolism. Post-assembly modifications refine the core scaffolds for bioactivity; for , cytochrome P450 oxidases (SnaA-C) dehydrogenate the macrolactone to introduce a key , converting inactive PIIB to active PIIA, while group B undergoes TE-catalyzed cyclodepsipeptidation. Engineering efforts have targeted these pathways for enhanced yields or novel analogs, such as overexpression of the acyltransferase VirI to boost virginiamycin M production 1.5-fold or mutasynthesis via snaE1 inactivation to generate phenylglycine variants in pristinamycin II. These modifications and genetic manipulations highlight the modularity of the systems for combinatorial biosynthesis.

Resistance

Mechanisms of resistance

employ several molecular strategies to resist streptogramins, primarily through enzymatic modification, efflux, and alterations to the ribosomal target site. These mechanisms are predominantly observed in Gram-positive pathogens such as staphylococci and enterococci, where resistance genes are often acquired via . Enzymatic inactivation represents a key resistance strategy, involving the chemical modification of streptogramin components to prevent their binding to the . Acetyltransferases encoded by vat genes, such as vat(A), vat(B), vat(D), and vat(E), acetylate the hydroxyl group at position 14 or 16 of group A streptogramins (e.g., dalfopristin), rendering them inactive by blocking their interaction with the peptidyl transferase center (PTC) of the 50S ribosomal subunit. This modification is specific to group A components and confers high-level resistance to the combination therapy, as group A inactivation disrupts the synergistic bactericidal effect with group B. For group B streptogramins (e.g., quinupristin), resistance occurs via lyase activity from Vgb proteins, which cleave the macrocyclic ring, linearizing the molecule and abolishing its ability to bind the ; this mechanism requires magnesium ions and is mediated by conserved residues in the . Enzymatic inactivation of group B is less common than for group A, with vgb genes identified mainly in staphylococci and streptococci. ABC-F subfamily proteins encoded by vga genes, including vga(A), vga(B), and vga(C), confer primarily to group A streptogramins and, to a lesser extent, group B in some variants; these proteins lack transmembrane domains and utilize to bind the empty 50S ribosomal subunit, inducing conformational changes in the center to dislodge bound antibiotics and rescue stalled ribosomes, thereby protecting translation from inhibition. In staphylococci, vga(A) expression increases minimum inhibitory concentrations (MICs) for pristinamycin IIA (group A) from 2 to 8 μg/ml and also affects due to overlapping specificity. These resistance systems are plasmid-borne, facilitating their , and are particularly prevalent in methicillin-resistant Staphylococcus aureus (MRSA) isolates from clinical and veterinary sources. Target site modification involves genetic alterations to the that diminish streptogramin binding affinity. Mutations in the rplV gene encoding ribosomal protein L22, located in the PTC, are a notable example; these include deletions (e.g., 6-bp removal of Gly79-Pro80), insertions (e.g., 15-bp addition of GPTLK at position 84), or duplications that disrupt the C-terminal β-hairpin structure, reducing binding by up to 80% as measured by fluorescence assays. Such changes elevate quinupristin-dalfopristin MICs 4- to 32-fold in S. aureus but spare intrinsic ribosomal function, with mutation frequencies around 10⁻⁸ under selective pressure. Ribosomal mutations are less frequent than enzymatic or efflux mechanisms due to the synergistic action of streptogramins, which requires coordinated binding of both groups to fully inhibit protein synthesis; isolated mutations often fail to confer complete to the combination. Resistance to streptogramins is largely acquired through , enabling rapid dissemination among . Genes encoding Vat and Vga proteins are frequently located on conjugative plasmids (e.g., pIP680 for vat(A), pKKS825 for vga(C)) or transposons (e.g., Tn5406 carrying vga(A)), which promote inter- and intra-species exchange via conjugation or in environments like the gut or animal reservoirs. This mobility is restricted to Gram-positives, with no significant transfer reported to Gram-negatives, and is enhanced by multiresistance plasmids that co-harbor genes for other antibiotics, amplifying selective advantages. L22 mutations, in contrast, arise chromosomally and are not horizontally transferable.

Prevalence and implications

Streptogramin resistance in (VRE) isolates from hospitals has been reported at rates of 10-25%, with a of clinical E. faecium strains indicating an overall prevalence of 24.1% (95% CI: 9.1–50.2%) for quinupristin-dalfopristin resistance across global studies including data up to 2022. In , resistance rates appear higher, particularly linked to historical veterinary use of virginiamycin in , with studies from countries like and showing elevated streptogramin-resistant enterococci in and prior to regulatory changes. Conversely, streptogramin resistance remains rare in community-acquired (MRSA), with susceptibility rates exceeding 99% in evaluated isolates. The implications of this resistance profile significantly restrict streptogramins, such as quinupristin-dalfopristin, to salvage options for multidrug-resistant VRE , where first-line agents like fail. This limitation has spurred programs aimed at optimizing streptogramin use to preserve efficacy, particularly in settings with high VRE burdens. Co-resistance with resistance genes, such as vanA alongside streptogramin-modifying genes like vat(E), further complicates treatment, as these elements often co-occur on mobile genetic platforms in clinical enterococci. Surveillance efforts, including WHO reports, have established links between animal agricultural practices and human streptogramin-resistant strains, highlighting transmission risks through food chains and environmental reservoirs. Following the 2006 ban on virginiamycin as a growth promoter, incidence of streptogramin resistance in enterococci from food animals declined notably; for instance, in , resistance in broiler E. faecium dropped from a peak of 66.2% pre-ban to 33.9% by 2000, representing approximately a 50% reduction in affected isolates. Looking ahead, the rising resistance trends underscore the need for novel antibiotic combinations, such as streptogramins paired with beta-lactams or efflux inhibitors, to restore therapeutic utility against resistant enterococci. Persistent gaps in global resistance mapping, as evidenced by limited streptogramin-specific data in systems like WHO's GLASS, hinder comprehensive surveillance and call for enhanced international monitoring.