Sulfur-containing microbial natural products and their role in communal interactions

Abstract

Natural products remain a primary source of new chemical entities and a central medium of biological communication. Among them, sulfur-containing natural products from microbes stand out for their diverse motifs—such as thioether (S–Cα/β/γ), thiazole, and sulfonate groups—distributed across RiPPs, NRPs, polyketides, lipids, terpenoids, and hybrids. These sulfur-containing metabolites functionally contribute to communal interactions—intra- and interspecies microbe-microbe and microbe-host interactions—through their antibacterial, antifungal, antiviral, anticancer, and immunomodulatory activities. Crucially, they may act as information-rich signals that tune quorum circuits, biofilms, membrane and ion homeostasis, and host pathways. This review provides a structure- and mechanism-guided overview of sulfur-containing natural products reported over the past decade (2014–2025), covering their microbial sources, chemical diversity, and mechanisms of action, and emphasizing how sulfur functionality encodes interaction strategies from microbiomes to environmental systems.

Graphical Abstract

Introduction

Natural products produced by microorganisms are an important resource in drug discovery for their chemical diversity and facilitation of microbe-microbe and microbe-host communication.^1–3 These information-rich small molecules advance strategies for competition, cooperation, and defense.

Within this landscape, sulfur-containing natural products occupy a particularly fertile niche.^4–6 Sulfur is woven through a striking diversity of microbial metabolites that cut across biosynthetic logics—ribosomally synthesized and post-translationally modified peptides (RiPPs), non-ribosomal peptides (NRPs), polyketides (PKs), lipids, terpenoids, and hybrid assemblies. Their structural motifs span thioethers (S–Cβ/α/γ), thiazol(in)e rings and thiopeptide macrocycles, thiolactones, disulfides, sulfoxides and sulfones, as well as sulfonate and sulfate functionalities. This chemical latitude underpins both scaffold and function diversity.⁷ Sulfur-containing natural products display a broad spectrum of communal interactions, from antimicrobial to immunomodulatory effects, quorum sensing and quenching, biofilm modulation, membrane and ion homeostasis remodeling, and cross-kingdom host signaling.^8,9 These compounds mediate behaviors within microbiomes that reverberate into environmental processes.

The past decade has seen a rapid expansion of this chemical and functional space. Genome and metagenome mining, targeted metabolomics, and advances in NMR/MS structure elucidation have uncovered new bond types and topologies in sulfur-containing natural products.^10–12 In parallel, mechanistic work has connected discrete sulfur motifs to specific molecular outcomes—such as lipid reorganization, ion-homeostasis collapse, translational arrest, and toll-like receptor (TLR) pathway modulation—bridging genotype, chemistry, and phenotype.

This review reports the communal interactions induced by representatives from each major sulfur-containing natural product class discovered in the last decade (2014–2025). We proceed from their biological sources and chemical diversity to their activities and mechanisms, with emphasis on how sulfur moieties enable intra- and interspecies interactions within environmental microbial communities and within animal and human microbiome contexts. By integrating chemistry with mechanisms, we aim to provide a coherent framework that will guide discovery, functional annotation, and rational engineering of the next generation of sulfur-empowered natural products.

1. Ribosomally synthesized and post-translationally modified peptides (RiPPs)

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a diverse and highly abundant superclass of natural products. RiPPs are first synthesized by the ribosome in the form of a precursor peptide (consisting of a leader and/or follower peptide and a core peptide) which is then modified by post-translational modification enzymes, ultimately yielding the mature RiPP after leader/follower peptide removal by a leader peptidase.¹³ Due to structural variation of the precursor peptide’s primary amino acid sequence and the numerous enzymatic modifications of the precursor peptide that are possible, RiPPs often possess highly distinct structures. Furthermore, because RiPP biosynthesis is largely dependent on the leader portion of the precursor peptide, the core peptide can be highly sequence diverse, even within the same RiPP subclass. The numerous sulfur-incorporating and sulfur-modifying post-translational modification enzymes involved in RiPP biosynthesis also enable the production of structurally diverse RiPPs. These post-translational modifications often directly contribute to the biological activities observed for RiPPs. In the subsections below, the chemical diversity and biological functions of RiPPs with different sulfur-containing functional groups are discussed.

1.1. Thioether containing RiPPs

Thioether crosslinks define a major tranche of RiPPs and are classified by the carbon atom bound to sulfur: S–Cβ, S–Cα, and S–Cγ (Figure 1 and Figures S1 and S2).¹³ These crosslinks hard-wire compact folds and precise binding surfaces, thereby determining membrane/lipid target recognition and, at the community scale, driving antagonism, colonization advantage, and signal interference.^14–17

Figure 1.

Structures of representative sulfur-containing RiPPs.

1.1.1. The S–Cβ thioether-containing RiPPs

The S–Cβ thioether-containing RiPPs are the most abundant and extensively characterized RiPP class, typically exemplified by lanthipeptides. In lanthipeptides, S–Cβ thioethers within (methyl)lanthionine bridges are generated via dehydration of serine and threonine residues into dehydroalanine (Dha) or dehydrobutyrine (Dhb), followed by intramolecular cysteine Michael addition, which builds multi-ring scaffolds.

Within this scaffold, recent studies reveal multiple modes of bioactivity and targets (Table 1). Nisin (1) (Figure 1 and Table 1) exemplifies a two-step, lipid II–dependent pore-forming mechanism in anti-Gram-positive bacteria: its N-terminal (methyl)lanthionine rings binding the pyrophosphate of lipid II, docking the peptide at the cell-wall interface; the C-terminal segment then inserts to nucleate lipid-II–stabilized pores, causing rapid membrane depolarization and bacterial death (Figure 2A).^18–20 By contrast, cacaoidin (2) and nukacin ISK-1 (3) (Figure 1 and Table 1) illustrate non-porating routes inhibiting cell-wall synthesis: 2 binds lipid II and directly inhibits the transglycosylase (Figure 2A),^21,22 whereas 3 primarily recognizing the pyrophosphate moiety of lipid II.²³ In both cases, transglycosylation is blocked, thereby halting peptidoglycan polymerization and cell-wall synthesis in Gram-positive organisms (Figure 2A). A complementary strategy targets non-cell-wall lipids: cinnamycin (4) and duramycin (5) use three S–Cβ bridges to form a pocket that binds the phosphatidylethanolamine (PE) headgroup, leading to PE reorganization and selective permeabilization of PE-rich membranes.^24–26 Cinnamycin (4) further induces transbilayer PE movement that facilitates the translocation and cell-surface exposure of annexin A2/A5,²⁵ while 5 blocks TIM1-mediated entry of enveloped viruses by masking virion-associated PE²⁶—extending this PE-targeting mechanism beyond bacteria.

Table 1.

Bioactive sulfur-containing RiPPs and the proposed targets

Compound(s)	Sulfur-containing Group	Species	Activity	Reference(s)
Nisin (1)	S–Cβ thioether	Lactococcus lactis	Anti-Gram-positive strains (including MRSA); via lipid-II–stabilized pore formation	18–20
Cacaoidin (2)	S–Cβ thioether	Streptomyces cacaoi	Anti-Gram-positive strains; via lipid-II sequestration and inhibition of cell wall transglycosylases.	21,22
Nukacin ISK-1 (3)	S–Cβ thioether	Staphylococcus warneri ISK-1	Anti-Gram-positive strains; via lipid-II sequestration blocks transglycosylation	23
Cinnamycin (4)	S–Cβ thioether	Streptomyces cinnamoneus	Antimicrobial activity against PE-rich Gram-positives; via phosphatidylethanolamine (PE) binding and PE-dependent membrane permeabilization	24,25
Duramycin (5)	S–Cβ thioether	Streptomyces cinnamoneus	Anti-Gram-positive strains; via PE headgroup recognition and selective permeabilization	26
Cebulantin (6)	S–Cβ thioether	Saccharopolyspora cebuensis	Anti-Gram-negative strains	39
Salivaricin A2, B (7, 8)	S–Cβ thioether	Streptococcus salivarius	Anti-inflammation; via STAT3 signaling inhibition	40
Salivaricin 10 (9)	S–Cβ thioether	Streptococcus salivarius	Anti-Gram-positive strains; via lipid-II targeting; pThr-dependent immune modulation and antibiofilm	41
Sh-lantibiotic-α (10), Sh-lantibiotic-P (11)	S–Cβ thioether	Staphylococcus hominis	Anti-Gram-positive strains (including MRSA)	42
Ruminococcin C (12)	S–Cα thioether	Ruminococcus gnavus	Anti-Gram-positive strains; via membrane perturbation, rapid PMF/ATP collapse	43–45
Hyicin 4244 (13)	S–Cα thioether	Staphylococcus hyicus 4244	Anti-Gram-positive strains (include MRSA); via membrane action and form antibiofilm	46
Thuricin Z (14)	S–Cα thioether	Bacillus thuringiensis	Anti-Gram-positive strains; via rapid membrane depolarization	47
Streptosactin (15)	S–Cα thioether	Streptococcus thermophilus	Antimicrobial activity the producer strain and close Streptococcus relatives with the same BGC	48
Enteropeptin A (16)	S–Cα thioether	Enterococcus cecorum	Antimicrobial activity against Enterococcus spp.; intra-genus antagonism	49
Thermocellin (17)	S-Cγ thioether	Clostridium thermocellum	Roles in quorum sensing and metabolic control	50
Lactocillin (18)	Thiazole	Lactobacillus gasseri JV-V03	Antimicrobial activity against Staphylococcus aureus, Enterococcus faecium, Corynebacterium aurimucosum, Gardnerella vaginalis, and multiple Streptococcus species	59
Cutimycin (19)	Thiazole	Cutibacterium acnes	Skin microbiome composition modulation, especially inhibition of Staphylococcus growth	60
Micrococcin P1 (20)	Thiazole	Bacillus cereus	Biofilm matrix production upregulation in Bacillus subtilis	62
Staphylococcus caprae AIP (21)	Thiolactone	Staphylococcus caprae	Inhibition of agr-mediated quorum sensing in Staphylococcus aureus	76

Figure 2.

Sulfur-containing RiPPs responsible for mediating bacterial communal interactions. (A) Interactions occurring in environmental microbiomes. (B) Interactions occurring in the human microbiome.

Across recent additions to the S–Cβ thioether–containing RiPPs landscape (Table S1), including bicereucin,²⁷ mathermycin,²⁸ kyamicin,²⁹ roseocin,³⁰ lexapeptide,³¹ andalusicin,³² CMB001,³³ bacinapeptins,^34,35 balucin,³⁶ lysinibacin,³⁷ and kunkecin A³⁸, antibacterial activity has been demonstrated predominantly against Gram-positive bacteria. Among these, kunkecin A, a nisin-type lantibiotic from Apilactobacillus kunkeei FF30–6 isolated from honeybees, exhibits narrow-spectrum yet potent activity against the honey bee pathogen Melissococcus plutonius³⁸ In contrast, cebulantin (6), from Saccharopolyspora cebuensis, exhibits selective anti–Gram-negative activity, inhibiting outer-membrane–compromised Escherichia coli (ΔlptD) and several Vibrio strains (e.g., V. cholerae, V. parahaemolyticus).³⁹

Beyond environmental and food-associated producer strains, the oral commensal Streptococcus salivarius produces salivaricin A2 (7) and salivaricin B (8), which interact with IL-6 and IL-21 to attenuate STAT3 signaling and thereby suppress STAT3-dependent inflammatory programs.⁴⁰ The same species also produces a set of phosphorylated S–Cβ thioether–containing RiPPs collectively termed salivaricin 10 (9), including SrnA1, SrnA2, and SrnA4, which combine targeted antibacterial and antibiofilm activities with immune modulation. A conserved N-terminal phosphothreonine (pThr) residue is required to elicit neutrophil chemotaxis and phagocytosis and to bias macrophages toward an M2 phenotype.⁴¹ Sh-lantibiotic-α (10) and Sh-lantibiotic-β (11), from the skin commensal Staphylococcus hominis A9, show selective activity against Staphylococcus aureus (including methicillin-resistant strains, MRSA) and act synergistically with the human cathelicidin LL-37 against Staphylococcus aureus, while sparing common skin commensals.⁴²

1.1.2. The S–Cα thioether-containing RiPPs

The S–Cα thioether linkages (sactionine) occur predominantly in sactipeptides (Figure 1). Such S–Cα linkages are installed by radical S-adenosylmethionine (rSAM) enzymes that couple the sulfur of an intramolecular cysteine to the α-carbon of another amino acid, thereby installing multiple sactionine thioether clamps of another amino acid.¹⁶ Although S–Cα–containing RiPPs constitute a relatively small family (Table 1),¹⁶ the past decade has seen rapid expansion in both membership and mechanistic insight. In 2019, ruminococcin C (RumC) (12) (Figure 1), from the human gut commensal Ruminococcus gnavus, was reported.^43,44 Structurally, RumC departs from classical S–Cα–containing RiPPs by adopting an unnested, double-hairpin topology stabilized by four S–Cα linkages, rather than a single nested hairpin. RumC exhibits antibiotic activity against Gram-positive pathogens (e.g., Clostridium perfringens, Bacillus subtilis) and can also induce a lag phase for Gram-negative bacteria Escherichia coli, meanwhile it did not impact human cell viability. Recently, Shamseddine et al. demonstrated that RumC does not form stable large pores but instead rapidly collapses cellular energetics—ATP depletion and loss of the proton-motive force—supporting a membrane-perturbation–driven, non-pore mechanism that reconciles the earlier intracellular phenotypes.⁴⁵ Additionally, Comparative analyses of the RumC isoforms reveal that differences in antibacterial potency (MIC) and spectrum correlate with subtle variations in their S–Cα crosslinking patterns.⁴⁵

Other recently reported S–Cα-containing RiPPs reinforce this membrane-centric theme (Figure S2). Hyicin 4244 (13)⁴⁶ from Staphylococcus hyicus displays anti-staphylococcal and antibiofilm activity consistent with membrane engagement. Thuricin Z (14)⁴⁷ from Bacillus thuringiensis induces rapid bacterial membrane depolarization and primarily targets Gram-positive bacteria, with a narrow spectrum centered on the Bacillus cereus group. Subsequently, streptosactin (15)⁴⁸ from oral Streptococcus spp. harbors two sequential four-residue sactionine macrocycles—an unusual, unnested topology within this family and shows potent but narrow activity restricted to the producer and its closest Streptococcus relatives that encode the same BGC, supporting a long-suspected fratricidal role in Streptococcus thermophilus populations. Enteropeptin A (16) from gut microbe Enterococcus cecorum introduces a thiomorpholine-type S–Cα thioether crosslink (with additional tailoring such as N-methylornithine) and exhibit intra-genus antagonism.⁴⁹

1.1.3. The S–Cγ thioether-containing RiPPs

The S–Cγ thioether, installed by rSAM enzymes, represents an emerging linkage in RiPPs. Initial evidence for S–Cγ thioether formation in RiPPs came from a distinctive class of precursor peptides termed SCIFF (Six Cysteines In Forty-Five), characterized by approximately six cysteines within a conserved C-terminal region of about 45-residue in the precursor.⁵⁰ An unambiguous S–Cγ chemistry was established in 2019 by Hudson et al. for the SCIFF peptide thermocellin (17) (Figure 1 and Table 1) from Clostridium thermocellum.⁵⁰ Functionally, SCIFF-derived ranthipeptides have been implicated in quorum sensing and metabolic control in solventogenic clostridia, suggesting an in situ signaling role for S–Cγ scaffolds.⁵¹ Recently, genome–metagenome surveys indicate that SCIFF/ranthi-like gene cassettes and SPASM-domain rSAM pathways are widespread and enriched in gut niches (e.g., Clostridia), yet only a limited set of S–Cγ products has been chemically validated to date.^52–55

1.2: Thiazol(in)e-containing RiPPs

Thiopeptides are a class of sulfur-rich RiPPs which contain several thiazol(in)e residues, in addition to a pyridine moiety, which collectively form a peptide with a macrocyclic region and a short tail region.⁵⁶ They are biosynthesized via YcaO-dependent cyclodehydration of a precursor peptide to form the thiazol(in)e moieities, followed by LanB-like dehydration of Ser/Thr to form Dha/Dhb residues and subsequent [4+2] cycloaddition of two Dha residues to form the pyridine ring, which completes the macrocycle prior to leader peptide cleavage.⁵⁷ Thiopeptides have complex structures and have been identified throughout nature, including in the human microbiome. Indeed, one of the founding bioinformatic studies of human microbiome-derived secondary metabolites identified diverse thiopeptide BGCs in metagenomic data throughout different anatomical regions of the human microbiome.⁵⁸ This included the thiopeptide antibiotic lactocillin (18) derived from the genome of Lactobacillus gasseri JV-V03, an isolate from the human vaginal microbiome. Compound 18 demonstrated nM minimum inhibitory concentration (MIC) against several notable human pathogens, including Staphylococcus aureus, Enterococcus faecium, Corynebacterium aurimucosum, Gardnerella vaginalis, and multiple Streptococcus species. Interestingly, Lactobacillus spp. are the most highly isolated bacterial species from the healthy human vagina.⁵⁹ Thus, the potent inhibitory activity of 18 against numerous pathogens may suggest that 18 plays an important role in combating vaginal bacterial infections and maintaining a healthy vaginal microbiome. Other thiopeptides have also been shown to contribute to interspecies competition in the human microbiome. Cutimycin (19), a thiopeptide from the abundant skin-associated Cutibacterium acnes, was shown to modulate the skin microbiome composition, particularly by inhibiting the growth of Staphylococcus, a bacterial genus that is also abundant in the skin microbiome.⁶⁰ Thiopeptides have also been found in other animal microbiomes, including in bacterial symbionts of fungus-gardening Trachymyrmex ants, where they likely play a role in combating ant pathogens.⁶¹ Besides their roles as antibiotics in interspecies warfare, thiopeptides have also been implicated in signaling-related activities (Figure 2A). A group of thiopeptide antibiotics known as thiocillins from Bacillus cereus were previously shown to induce biofilm matrix production in Bacillus subtilis.⁶² This included the thiocillin micrococcin P1 (20), which, like other thiopeptides, also possessed antimicrobial activity via inhibition of translation.^63,64 Importantly, however, the antibiotic activity and biofilm induction activity of thiocillins were shown to be independent of each other, as a mutated 20 that lost its antibiotic activity due to the mutation was shown to retain its biofilm induction activity. Furthermore, other bacteria that contained thiopeptide BGCs in their genomes were also shown to be capable of inducing B. subtilis biofilm matrix production during coculture with B. subtilis. This intriguing discovery suggested that 20, and likely numerous other thiopeptides, are capable of interacting with multiple targets, including the ribosome to exert antimicrobial activity as well as other non-ribosomal targets to influence biofilm production.

1.3: Thiolactone-containing RiPPs

Besides their roles in direct interspecies competition in microbiomes, RiPPs can have more indirect effects on the populations of other microbes. One such class of non-antibiotic RiPPs that influences nearby microbes is the class of autoinducing peptides (AIPs). AIPs are short peptides 7–12 amino acids in length which contain a lactone or thiolactone cyclization, forming a five-residue macrocyclic structure.^65,66 AIPs have been identified across diverse bacterial phyla, with bioactivities including pathogenic biofilm inhibition and modulation of microbiome composition against pathogenic species such as those from the genera Paramuribaculum, Oscillospiraceae, Heminiphilus, and Prevotella.⁵³ However, the most well-studied AIPs are those from Staphylococcus spp., particularly Staphylococcus aureus. There are four known AIPs produced by S. aureus – AIP-I through AIP-IV – which all contain a thiolactone formed between a Cys residue and the C-terminal carboxylate. S. aureus AIPs are well-known for their roles in quorum sensing via the activation of the agr operon in S. aureus, which contributes to global upregulation of virulence factors.^67–71 The role of S. aureus AIPs in quorum sensing and controlling virulence is arguably more influential to microbial populations than the influence of antimicrobial metabolites, as the upregulation of virulence genes in Staphylococcus spp. enables their survival and overcolonization in the human microbiome, which not only allows for initial infection, but can contribute to recurrent infections.^72–75 Conversely, however, AIPs secreted by other Staphylococcus species (non-cognate AIPs to S. aureus) have been shown to downregulate virulence in S. aureus. The AIP from Staphylococcus caprae (21) – which contains a thiolactone formed between C4 and F8 of the peptide (YSTCSYYF) – was shown to inhibit agr-mediated quorum sensing in S. aureus, which contributed to the prevention of methicillin-resistant S. aureus (MRSA) infections from progressing in a mouse model.⁷⁶ This interspecies regulatory activity of 21 acting on S. aureus is distinct from the activity of native S. aureus-produced AIPs, such as AIP-I (YSTCDFIM), in controlling S. aureus virulence, demonstrating the biological versatility of thiolactone-containing AIPs (Figure 2B).

2. Non-ribosomal peptides (NRPs)

Through incorporation of non-proteinogenic amino acids, non-ribosomal peptides (NRPs) offer expanded structural diversity compared to their ribosomally synthesized counterparts, and a broad range of activities.⁷⁷ NRPs typically acquire their sulfur through the incorporation of methionine or cysteine, as specified by an adenylation (A) domain of NRP synthetase (NRPS). A cysteine residue may be acted on by a cyclization (Cy) domain to form thiazoline heterocycles, which may be oxidized to form thiazoles or reduced to form thiazolidines. Alternatively, tailoring enzymes acting upon the NRP in trans (i.e. outside of the canonical NRPS) can bestow unique sulfur-containing groups such as thioketones and acylsulfenic acid.^78,79

NRPs are often employed for defensive action, such as through antibacterial or antifungal activities. In the human microbiome, some antimicrobial NRPs additionally modulate the host immune response to combat invading species. Also common are NRP metallophores used for metal homeostasis and to outcompete other organisms in metal-limited environments. In many of these cases, the sulfur moiety of these compounds plays an important role in target recognition and metal chelation.^80,81 This section will highlight recently discovered examples of sulfur-containing NRPs and polyketide-NRP hybrids (PK-NRPs) (Figure 3) and their diverse communal activities (Table 2).

Figure 3.

Chemical structures of representative NRPs and PK-NRPs.

Table 2.

Sulfur-containing NRPs and PK-NRPs and their activities as described in this section.

Compound(s)	Sulfur-containing group	Species	Activity	Reference(s)
Bacillothiazols (22–26)	Polythiazole	Bacillus velezensis FZB42	PTP1B inhibitor; implicated in Bacillus swarming	83
Mupirochelin (27)	Thiazole, thiazoline	Pseudomonas sp. NCIMB 10586	Metallophore; anti-oomycete activity	84
Mutanobactins (28), mutanolins	Thiazepanone	Streptococcus mutans UA159	Inhibits hyphal formation of Candida albicans; induces cytokine (IL-6, IL-12) release	87–89
Mutanofactins (29)	Thiazole	Streptococcus mutans	Promotes intra- and interspecies biofilm formation	90,91
Lugdunin (30)	Thiazolidine	Staphylococcus lugdunensis	Anti-Gram-positive activity via membrane breakdown; TLR2 agonist	92,93
Sadopeptin A, B (31, 32)	Methionine sulfoxide (S=O)	Streptomyces sp. YNK18	Proteasome inhibitor	94
Ecteinamines (33, 34)	Methionine sulfoxide, sulfanediol, thiazoline	Micromonospora sp. WMMB482	Broad-spectrum metallophore	95
Sulfenicin (35)	Acylsulfenic acid, thiazole	Streptomyces sp. CNT360	Broad-spectrum metallophore	79
Thiolactomycin (36)	Thiolactone	Lentzea sp. ATCC 31319	Anti-Gram-positive, anti-Gram-negative, anti-protozoal activity via type II fatty acid synthase inhibition	96,97
Forazoline A (37)	Thioketone (S=C), thiazoline	Actinomadura sp. WMMB-499	Antifungal activity via membrane permeabilization	78,98
Collismycin A, C (38, 39)	Methyl sulfide (S-CH3)	Streptomyces sp. MC205, S. sp. MQ22	Anti-cancer and anti-biofilm activity via metal starvation (metallophore)	99,100

2.1. S,N-heterocycle-containing NRPs

Thiazole-producing NRPS biosynthetic gene clusters (BGCs) often encode bioactive molecules, which make them good search targets for BGC prediction tools such as antiSMASH.⁸² Bacillothiazols (22–26) from the rhizobacterium Bacillus velezensis FZB42 were recently discovered via this method. These compounds feature three consecutive thiazoles that are oxidized iteratively by the tailoring enzyme NrsB, as opposed to in cis oxidase domains. Bacillothiazols were found to be strong inhibitors of protein tyrosine phosphatase PTP1B. Additionally, heterologous expression of the bacillothiazol BGC, nrs, in B. subtilis resulted in reduced swarming, hinting at the potential activity of the compound in its native strain.⁸³ Another intriguing polythiazole-containing NRP is mupirochelin (27), produced by soil bacterium Pseudomonas sp. NCIMB 10586. This compound has moderate iron-chelating activity, but when not complexed with metal ions, it also displays anti-oomycete activity against Globisporangium ultimum, a pathogen found in the bacterium’s native environment.⁸⁴ From the human microbiome, it was recently discovered that Streptococcus salivarius K12 produces thiazolidine-containing PK-NRPs termed salivabactins with potent bactericidal activity against Gram-positive strains, though the exact mechanism is currently unclear.^85,86

In the human oral microbiome, Streptococcus mutans UA59 produces mutanobactins and mutanolins to combat the colonization of pathogenic fungus Candida albicans.^87–89 These PK-NRP hybrids, characterized by their unique seven-membered thiazepanone ring, were found to inhibit the transition of C. albicans from its yeast form to its invasive mycelial form. Additionally, mutanobactin B (28) was found to significantly promote the release of pro-inflammatory cytokines IL-6 and IL-12 from human macrophages (Figure 4), yet decreases release of other such cytokines such as MCP-1 and G-CSF. This activity is specific to the sulfur-containing peptide portion of mutanobactin, as it is not displayed by the mutanamide intermediate, which lacks the cysteine moiety.⁸⁹ These results warrant further study of the role immunomodulation by mutanobactins may play in combating C. albicans. S. mutans also produces NRPs to promote the biofilm formation of itself and related human commensal species Streptococcus gordonii and Streptococcus oralis, namely the thiazole-containing mutanofactin (Muf) family. Muf-697 (29) in particular was found to alter the morphology of the hydrophilic mucin layer that protects the oral cavity, exposing the hydrophobic surface and allowing for increased bacterial adhesion. This activity works in tandem with the biofilm-promoting effects of mutanofactins to establish S. mutans as an early colonizer of the human oral microbiome.^90,91

Figure 4.

Models of sulfur-containing NRPs mutanobactin B (28) and lugdunin (30) from human commensals being used to combat invading species. In the oral microbiome, Streptococcus mutans produces mutanobactin B (28) to inhibit the transition of Candida albicans to its invasive hyphal form and induce pro-inflammatory cytokine release from macrophages. In the skin microbiome, lugdunin (30) is released by Staphylococcus lugdunensis to kill S. aureus, work cooperatively with human AMPs, and induce cytokine release from primary human keratinocytes.

Similarly to mutanobactins from S. mutans, Staphylococcus lugdunensis produces the NRP lugdunin (30) to combat Staphylococcus aureus in the human skin and nasal microbiomes.^92,93 Lugdunin, a macrocyclic peptide containing a thiazolidine ring, is a potent bactericidal agent against S. aureus and other Gram-positive bacteria. This effect is cooperative with human antimicrobial peptides (AMPs) such as LL-37 and DCD-1(L), and lugdunin increases the expression of these host AMPs. In addition, lugdunin was found to induce release of pro-inflammatory cytokines from several cell types—for instance, induction of CXCL8 release via interaction with toll-like receptor 2 (TLR2) on primary human keratinocytes—leading to the recruitment of neutrophils and monocytes. The combination of direct killing, cooperativity with host AMPs, and the action of phagocytic immune cells prevents S. aureus colonization.⁹³ These examples of mutanobactin B (28) and lugdunin (30) showcase how multifunctional, sulfur-containing NRPs can be used by human commensal bacteria to mobilize the host immune system (Figure 4).

2.2. S-O bond-containing NRPs

A wide variety of sulfur-containing functional groups can be added to an NRP in trans, such as those with sulfur-oxygen bonds. For instance, the recently discovered NRP families of sadopeptins (31–32) and ecteinamines (33–34) contain methionine sulfoxide (Met(O)), among other uncommon functional groups.^94,95 Sadopeptin A and B (31–32) were isolated from Streptomyces sp. YNK18 after a targeted search for mass spectroscopic signatures of sulfur-bearing compounds. 31 and 32 were found to be potent proteasome inhibitors with a distinct effect compared to known inhibitors that did not involve autophagic flux or apoptosis, thus suggesting potential use as antimicrobial compounds.⁹⁴ Ecteinamines P and A (33–34) produced by marine bacterium Micromonospora sp. WMMB482 feature sulfanediol (33), thiazoline, and Met(O) (34) groups. They were found to be broad-spectrum metallophores, chelating iron, copper, nickel, zinc, and cobalt.⁹⁵ Another intriguing S-O functional group, acylsulfenic acid, was recently found to be naturally synthesized by marine Streptomyces sp. CNT360 in the PKNRP sulfenicin (35). The biosynthetic S-hydroxylation enzyme (TaaH) is broadly distributed across bacterial phyla, including in four other BGCs, indicating the group may be an important structural feature of multiple natural products. 35 appears to function as a broad-spectrum metallophore, and further investigations into its biological activity are ongoing.⁷⁹ As with the previously discussed with mupirochelin (27), it is possible these complex metallophores have additional interactions with specific competitors in the producing organism’s native environment.

2.3. Other sulfur-containing NRPs

Some known sulfur-containing NRPs have only recently had their biosynthesis or bioactivities elucidated. For instance, the unique γ-thiolactone ring of antibacterial thiolactomycin (36) was determined to be synthesized via an unusual sulfuration by an NRPS Cy domain (TlnC_Cy) and subsequent cyclization by a cytochrome P540 enzyme (TlnA).⁹⁶ Thiolactomycin specifically inhibits type II fatty acid synthase FabB/FabF, thus giving it potent activity against Gram-positive and Gram-negative bacteria, and protozoans (e.g. Plasmodium falciparum, Trypanosoma brucei). The γ-thiolactone ring is essential to this activity, as it mimics the orientation of the thiomalonate substrate required for fatty acid synthesis.⁹⁷ Forazoline A (37) is a novel PK-NRP antifungal from Actinomadura sp. WMMB-499 that was initially predicted to contain a sulfoxide group, but a revision of the mass spectrometry data revealed it contained a unique thioketone group instead.⁷⁸ Forazoline A causes permeabilization of the fungal membrane and has synergy with antifungal compound amphotericin, indicating a distinct mechanism of action.⁹⁸ Lastly, the methyl-sulfide-containing collismycins (38, 39) have been extensively studied for their diverse bioactivities. For example, collismycin C (38) has been shown to inhibit biofilm formation of S. aureus, while collismycin A (39) inhibits proliferation of cancer cells. Both activities have been linked to the iron-chelating activity of collismycins, as they limit the iron that is available for cell growth.^81,99,100 Such studies showcase the versatility of sulfur-containing NRPs, allowing their native producers to outcompete other species both by direct (e.g. antibacterial, antifungal) and indirect (e.g. immunomodulatory, metal-starving) interactions.

3. Polyketides (PKs) and Lipids

Though sulfur incorporation is relatively less common than in peptides, the well-established signaling properties of polyketides and lipids translate to their sulfur-containing analogs.^101–103 Sulfur incorporation in these compounds can come from a variety of sources, including but not limited to amino acids, enzymatic sulfation, and sulfur-containing small molecules.^104–107 The varied signaling activities of these sulfur-featuring molecules reflect their structural diversity (Figure 5). Though these compounds may be sourced from environmental microbiomes (e.g. endophytic, marine) in addition to the human microbiome, modulation of the human immune system is a common target for lipid and PK-based drug discovery, with the anti-inflammatory activities of prunomarin A (40) and rubterolone N (42) exemplifying this trend.^108,109 Besides this route, neosartyone (41) can inhibit lipid accumulation in HepG2 liver cells and oxazolismycin (43) has been explored as a potential treatment for high blood pressure as an angiotensin-converting enzyme (ACE) inhibitor.^110,111 These promising activities warrant further elucidation of the affected signaling mechanisms, which will be explained through the remainder of this section. The next paragraphs, organized by the featured chemical bond, will highlight several prominent sulfur-containing lipids and polyketides and explore their signaling activities in detail (Figure 6).

Figure 5.

Representative structures of sulfur-containing PK and lipid signaling natural products.

Figure 6:

Highlighted sulfur-containing PKs and lipids and their signaling activities. The color blocks correspond to the source of the producing strain. RNS: reactive nitrogen species.

3.1. Thioether and Sulfoxide-containing PKs

A large-scale screening study of 5,000 fungal samples using a Signal Transducer and Activator of Transcription 3 (STAT3) activity assay carried out by Li et. al. identified a fraction generated from Paraphaeosphaeria neglecta FT462, fungus that resides in the Hawaiian plant Lycopodiella cernua, which exhibited notable STAT3 inhibition. Bioassay-guided fractionation led to the isolation of three novel metabolites, including one that featured a rare γ-pyranone–γ-lactam–1,4-thiazine skeleton, termed paraphaeoispearide A.¹¹² Although this sulfur-containing polyketide was not attributed to the observed STAT3 inhibition, a subsequent study revealed two additional sulfur-containing derivatives, paraphaeoispearides E and G (44 and 45).¹¹³ As opposed to the heterocyclic thiazine moiety seen in paraphaeospearide A, the sulfur atoms in 44 and 45 were instead situated on a mercaptolactate-derived backbone. In 44, this sulfur appeared as a sulfide, while 45’s sulfur featured as a sulfoxide. 44 and 45 both downregulated the expressions of nuclear factor-κB (NF-κB) and inducible nitric oxide synthase (iNOS) without notable cytotoxicity, suggesting an important role of the linear geometry of the sulfur-containing moieties to enable their signaling properties. 45’s increased potency against NF-κB and iNOS further emphasized the potential role of the sulfoxide group in mediating these immunological phenomena (Figure 6).¹¹³ The fundamental role of NF-κB signaling to induce inflammation suggest that 44 and 45 could be promising candidates as immunomodulatory drugs, such as chemopreventative drugs.

3.2. Disulfide-containing PKs

Han et. al. employed modified culture parameters to induce the production of dipenirestones which feature disulfide-linked resorcylic acid lactones (RALs). These sulfur-linked dimers, which were produced through the addition of DMSO and sea salt to a marine Pencillium sp. culture, exhibited notable anti-proliferative activity and apoptosis in the human gastric cancer cell line HGC-27, prompting further investigation into their anti-cancer activity. Depenirestone A (46) was found to arrest the cell cycle in the HGC-27 cells, leading to investigations into its effects on the P13K/AKT/mTOR signaling pathway due to its important role in mediating cell survival, proliferation, and cell cycle progression.¹⁰⁷ Molecular docking simulations suggested that 3 could strongly interact with P13K and western blotting confirmed that both RAL dimers could inhibit the activation of P13K, AKT, and mTOR to induce their anti-proliferative effects. These results were corroborated by reduced cell cycle regulatory protein (Cyclin E and Bcl-2) and increased apoptotic marker (Cleaved Caspase 3 and Bax) expressions, illustrating an elaborate signaling cascade influenced by 46 that intertwines cell cycle arrest and apoptosis to induce an anti-cancer effect (Figure 6).¹⁰⁷

3.3. Sulfonate-containing Lipids

As microbial mimics of human endogenous sphingolipids, sulfonate-containing bacterial sulfonolipids (SoLs) have been established as important mediators of Toll-like Receptor 4 (TLR4)-mediated inflammation in human disease. An earlier elucidated the unique biosynthetic enzymes underlying SoL production, namely a cysteate synthase (Cys), a cysteate fatty acyltransferase (CFAT), and a short-chain dehydrogenases/reductase (SDR).^114,115 Biosynthetic enzyme-guided correlation of these enzymes using multi-omic gut microbiome data from inflammatory bowel disease (IBD) datasets found a consistent negative correlation with the abundance of SoL-producing bacteria (e.g., Alistipes, Chryseobacteriun, and Odoribacter), SoL-synthesizing enzymes, and SoL abundance, which was confirmed in an IL10^−/− and proxicam-induced colitis mouse model.^115,116 Given their structural similarities to lipid A, the immunogenic component of lipopolysaccharide, (LPS), prompted their investigations in mediating TLR4-dependent signaling. Molecular docking of sulfobacins A and B (47 and 48) supported the binding of multiple SoLs to the TLR4/MD-2 complex, which was confirmed with an ELISA displacement assay.¹¹⁵ While SoLs could induce mild IL-6, TNFα, and IL-1β gene expressions when administered alone, Co-treatment with LPS saw a dramatic decrease in inflammatory cytokine expression compared to LPS treatment. Further western blotting found that SoL treatment decreased LPS-induced ERK1/2 and p38 expressions and IκBα degradation, all of which occur downstream of the TLR4 signaling (Figure 6).^114,115 Besides influencing this pathway to mitigate host gut disease-related inflammation, a subsequent study also found that colonization by SoL-producing bacteria could modulate the host lipidome, potentially enabling further protective signaling effects outside TLR4.¹¹⁶ Collectively, these studies established an emerging class of immunoregulatory sulfonate-containing lipids produced by human microbiota that protect against gut inflammation.

3.4. Sulfate-containing Lipids

In contrast to the anti-inflammatory activity of the sulfobacins, the sulfur-containing glycolipid sulfolipid-1 (49) produced by pathogenic Mycobacterium tuberculosis strains has been garnering attention as a potential virulence factor. The sulfate group is installed on a trehalose by sulfotransferase (Stf0) prior to extensive acylation reactions.¹¹⁷ As the causative agents of pulmonary tuberculosis, Ruhl et. al. found that M. tuberculosis and organic extracts of the bacteria could induce cough in guinea pigs. Non-virulent strains that did not produce 49 could not replicate these results, prompting their investigation into 49’s potential cough-inducing mechanism. Besides increasing cough in guinea pigs upon nebulization, 49 could activate mouse and human dorsal root ganglion (DRG) and nociceptive neurons, as indicated by dramatically increased intracellular [Ca²⁺] following treatment. This increase occurred at the same level in Ca²⁺-free media, thus suggesting that the influx of Ca²⁺ was derived from intracellular pools. These results were only observed in capsaicin-responsive neurons expressing transient receptor potential cation channel subfamily V member 1 (TRPV1⁺). These combined results suggest that 49 can agonize TRPV1 and promote Ca²⁺ influx into TRPV1⁺ neurons to induce cough during M. tuberculosis infections (Figure 6).¹¹⁷ The characterization of 49’s cough-inducing activity presents a novel aspect of M. tuberculosis infection pathogenesis that can be targeted in future drug development programs.

4. Terpenes and Others

4.1. Terpenes

The incorporation of sulfur into terpenoids is relatively less common compared to ribosomal peptides (RiPPs), non-ribosomal peptides (NRPs), and polyketides (PKs). However, recent studies have unveiled a series of structurally unique sulfur-modified terpenoids with significant biological functions (Figure 7 and Table 4). These compounds, primarily isolated from endophytic and marine fungi, play a crucial role in mediating their bioactivities. In many cases, the biosynthetic enzyme or method for incorporation of sulfur into these rare compounds is unknown or unclear.^6,101

Figure 7:

Representative structures of sulfur-containing terpenes and other signaling natural products.

Table 4.

Sulfur-containing terpenes and others with bioactivities

Compound(s)	Class	Sulfur-containing Group	Species	Activity	Reference(s)
Leptosphin A (50)	Terpenes	Sulfide	Leptosphaeria sp. XL026	Antimicrobial activity against Rhizoctonia cerealis and Bacillus cereus	118
Pseudallenes A (51) and B (52)	Terpenes	Sulfide	Pseudallescheri a boydii CS-793	Plant pathogen inhibition against Gaeumannomyces graminis, Colletotrichum gloeosporioides, Alternaria solani	119
(7S)-flavilane A (53)	Terpenes	Sulfoxide	Aspergillus sydowii 10–31	Microalgae inhibition against Prorocentrum sp.; anti-Gram-negative activity against Vibrio sp.	120
(7S)-4-iodo-flavilane A (54)	Terpenes	Sulfoxide	Aspergillus sydowii 10–31	Microalgae inhibition against Prorocentrum sp.; anti-Gram-negative activity against Vibrio sp.	120
Ovothiol A (55), B (56), and C (57)	Others	Thiol	Sea urchin eggs, marine organisms, including invertebrates, microalgae, and bacteria.	Antioxidant, anti-inflammatory, cardioprotective, gastroprotective, and photoprotective activities; redox homeostasis (GSH cooperation), photochemical reduction, oxidative stress regulation (↑GSH, ↑CAT, ↓MDA, ↓NO), modulation of NF-κB and apoptotic signaling pathways	121–125
Violaceimides A-D (58–61)	Others	Sulfide	Aspergillus violaceus	Selective inhibitory effects against human leukemia U937 and human colon cancer HCT-8 cells	126
Ochrathinols A and B (62, 63)	Others	Sulfide	Aspergillus ochraceopetalif ormis	Anti-inflammatory activity by suppressing pro-inflammatory cytokine (IL-1β, IL-6, and TNF-α) release and restoring NAD+/NADH balance	127
Tropodithietic acid (64)	Others	Disulfide	Phaeobacter inhibens and P. piscinae	Broad-spectrum antibacterial activity; disturb metabolic and stress-response pathways in target bacteria, inducing oxidative-stress and iron-uptake genes; regulates gene networks associated with motility, biofilm formation, and secondary metabolism; reshape microbial community composition and contribute to ecological stability	128–130

4.1.1. Sulfide-containing Terpenes

Leptosphin A (50) is a novel sulfur-containing sesquiterpenoid isolated from the endophytic fungus Leptosphaeria sp. XL026, representing the first example of a sulfur-substituted eremophilane sesquiterpenoid. It exhibits moderate antibacterial activity against the plant pathogens Rhizoctonia cerealis and Bacillus cereus, providing a new scaffold for the discovery of novel antimicrobial agents.¹¹⁸ Pseudallenes A (51) and B (52) are two new sulfur-containing ovalicin sesquiterpenoid derivatives discovered from the deep-sea cold seep fungus Pseudallescheria boydii CS-793. These compounds are exceptionally rare examples of sulfur-modified ovalicin derivatives, which showed broad-spectrum inhibitory activity against various plant pathogens, including Gaeumannomyces graminis, Colletotrichum gloeosporioides, and Alternaria solani, with MIC values ranging from 2 to 16 μg/mL.¹¹⁹

4.1.2. Sulfoxide-containing Terpenes

The cold-seep fungus Aspergillus sydowii 10–31 yielded two rare sulfoxide-containing sesquiterpenoids, namely the known (7S)-flavilane A (53) and the new (7S)-4-iodo-flavilane A (54). Notably, compound 54 is unique due to its incorporation of an iodine atom. These compounds demonstrated inhibitory effects against the harmful microalgae Prorocentrum micans and Prorocentrum minimum, as well as the bacteria Vibrio anguillarum, Vibrio harveyi, Vibrio parahaemolyticus, and Vibrio splendidus.¹²⁰

4.2. Others

4.2.1. Thiol-containing Others

Ovothiols, particularly ovothiol A (55), B (56), and C (57), are a unique class of sulfur-containing natural products. The most notable structural feature of these compounds is the 5-thiolhistidine moiety, a histidine ring containing a thiol group (Figure 7). First isolated from sea urchin eggs, they are now found in a wide range of marine organisms, including invertebrates, microalgae, and bacteria. The widespread distribution of ovothiols and their distinct chemical properties suggest that they play a central role in the cellular biochemistry and survival of marine ecosystems. While ovothiols are far from being simple antioxidants, their unique structure allows them to act as versatile molecular messengers, subtly regulating communal interactions both within and between cells, and even across different species. For instance, their oxidized forms can directly inhibit key metabolic enzymes in microalgae, indicating their role as molecular switches in a cell’s response to environmental signals like light.¹²¹

In terms of redox homeostasis, the low pKa thiol group of ovothiols makes it an efficient antioxidant, capable of rapidly scavenging reactive oxygen and nitrogen species (ROS/RNS) to protect cells from oxidative damage. Its unique redox potential allows it to form a sophisticated cooperative system with glutathione (GSH), where ovothiols quickly eliminates peroxides, and the resulting ovothiols disulfide can then be reduced by the more potent GSH.¹²² Recent research has also unveiled the photochemical reduction properties of ovothiols: their disulfide form can be converted back to the reduced form upon exposure to UVA light. The reduced form exhibits stronger UVA absorption and a barrier effect, thereby reducing UVA-induced oxidative damage to proteins and lipids.^121,123 These findings reveal the multifaceted roles of ovothiols in environmental stress response and intracellular signaling.

The unique chemical and biological functions of ovothiols have opened up significant prospects in pharmacology. Recent studies have confirmed their powerful antioxidant and anti-inflammatory activities, exploring their therapeutic potential in various disease models. In a rat myocardial infarction model induced by epinephrine, oral administration of ovothiol A significantly improved electrocardiogram abnormalities and restored a variety of biomarkers by enhancing antioxidant indicators like GSH and catalase (CAT) while reducing oxidative stress markers such as malondialdehyde (MDA) and nitric oxide (NO).^121,124 Similarly, in an ethanol-induced rat gastric ulcer model, ovothiol A promoted ulcer healing by scavenging free radicals, inhibiting inflammation, and regulating cell apoptosis.¹²⁵ The consistency across these studies suggests that the core therapeutic mechanism of ovothiols in various disease models is closely linked to their potent antioxidant and anti-inflammatory capabilities (Figure 8A).

Figure 8.

Other sulfur-containing natural products responsible for mediating bacterial communal interactions. (A) Thiol-containing others and their proposed signaling activities; (B) Disulfide-containing others and their proposed signaling activities.

4.2.2. Sulfide-containing Others

Violaceimides A-D (58-61), from the sponge-associated fungus Aspergillus violaceus, demonstrate selective inhibitory effects against human leukemia U937 and human colon cancer HCT-8 cells, with low cytotoxicity to Vero cells, highlighting their potential as therapeutic agents.¹²⁶ Also classified as thioethers are ochrathinols A and B ((±)-62 and (±)-63), a pair of previously unreported sulfur-containing racemates isolated from the antarctic soil fungus Aspergillus ochraceopetaliformis.¹²⁷ These compounds have a novel structure featuring a 3-methylhexahydro-2H-cyclopenta[b]thiophene core. Interestingly, ochrathinol A ((±)-65) remarkably suppressed the release of LPS-induced pro-inflammatory cytokines (such as IL-1β, IL-6, and TNF-α) at a concentration of 10 μM. It also effectively alleviated the unbalanced NAD+/NADH ratio caused by LPS in RAW264.7 macrophages, demonstrating strong anti-inflammatory activity.

4.2.3. Disulfide-containing Others

Tropodithietic acid (TDA, 64), a sulfur-containing seven-membered aromatic natural product produced by members of the marine family Rhodobacteraceae (such as Phaeobacter inhibens and P. piscinae), exhibits broad-spectrum antibacterial activity. It effectively inhibits several marine and opportunistic pathogens, including Vibrio anguillarum, V. vulnificus, and Pseudomonas aeruginosa.¹²⁸ Recent studies have further revealed that sub-inhibitory concentrations of TDA disturb metabolic and stress-response pathways in target bacteria, notably inducing oxidative-stress and iron-uptake genes.¹²⁹ Beyond its antimicrobial effect, TDA acts as a signaling molecule within its producers and neighboring microbes. Transcriptomic analyses demonstrated that TDA regulates gene networks associated with motility, biofilm formation, and secondary metabolism, largely overlapping with those controlled by acyl-homoserine lactone quorum-sensing systems, suggesting a coordinated regulatory interplay.^128,130 Moreover, TDA has been shown to reshape microbial community composition and contribute to ecological stability, underscoring its dual role as both an antibiotic and a chemical signal in marine microbial ecosystems (Figure 8B).¹²⁸

Conclusion

This review consolidates discoveries from the past decade in microbial sulfur-containing natural products across RiPPs, NRPs, polyketides, lipids, terpenoids, and hybrids that regulate various communal interactions. Across these classes, the mechanisms converge on high-value nodes of cellular physiology and communication: lipid II and membrane engagement, ribosomal and translation inhibition, ion-homeostasis and envelope remodeling, quorum-circuit rewiring and biofilm control, host immune modulation, and metal/redox homeostasis interference. This breadth positions these sulfur-containing metabolites as candidates for new anti-infectives, antivirals, immunomodulators, and adjuvants, as well as precision tools for perturbing microbiomes. The last decade has seen advancements in genomic mining tools that enable the targeting of BGCs encoding sulfur moieties, and improved methodologies for identifying and isolating sulfur-containing natural products by their specific spectroscopic signals. As drug discovery technologies continue to advance, sulfur-containing natural products remain a relevant and diverse source of bioactive and signaling compounds with potent therapeutic potential.

Supplementary Material

Additional compound structures (Figure S1, S2) and biological information (Table S1) (DOCX)

Table 3. Sulfur-containing lipids and PKs with signaling activities.

The bolded compounds are highlighted throughout the section and in Figure 6.

Compound(s)	Class	Sulfur-containing Group(s)	Species	Activity	Reference(s)
Prunomarin A (40)	PK	Sulfoxide	Phomopsis prunorum (F4–3)	Anti-NO production	108
Neosartyrone (41)	PK	Methylsulfonate	Neosartorya udagawae HDN13–313	Anti-lipid accumulation	109
Rubterolone N (42)	PK	Thiazolidine	Actinomadura sp. 5–2	Anti-mPGES1	110
Oxazolismycin (43)	PK-NRP	Methylthiol	Streptomyces griseochromogenes ATCC 14511	Anti-ACE	111
Paraphaeospharides (44, 45)	PK-NRP	Thioether, Sulfoxide	Paraphaeosphaeria negelcta FT462	Anti-NFκB, anti-iNOS	113
Dipenirestone A (46)	PK	Disulfde	Penicillium sp.	Anti-PI3K, anti-Akt, anti-mTORC1	107
Sulfobacins (47, 48)	Lipid	Sulfonate	Chryseobacterium gleum DSM16776, Alistipes timonensis DSM27924	LPS displacement from TLR4	114–116
Sulfolipid-1 (49)	Lipid	Sulfate	Mycobacterium tuberculosis Erdman	TVRP1 agonist	117