Bacteria are known to be very versatile organisms, able to colonize a variety of environments. One such environment is the human organism, which they colonize and infect opportunistically or non-opportunistically, using their virulence factors, causing a variety of symptoms and diseases. This creates a number of challenges to overcome and treat such infections (Reizer et al. 1996).
However, these infections are possible for the bacteria only due to their mastery of utilizing metabolic pathways, allowing them to be flexible and adapt to the current conditions. Fortunately, we have managed to understand, harness, and apply these bacterial abilities, eg. to design safe and effective strains that generate a wide range of novel biological products. Unfortunately, this features also allows pathogenic bacteria to quickly gain an advantage over our therapy. The most noticeable advantage nowadays being growing bacterial drug resistance, and our relative inability to counter it in clinical conditions (Reizer et al. 1996).
One of the metabolic pathways responsible for creating substrates that are used by bacteria, to develop their virulence factors, is the use of amino sugars which are a variety of complex monosaccharides in which hydroxyl group is replaced by amine group (Reizer et al. 1996). Most of the research on bacterial metabolism of amino sugars comes from studies with Escherichia coli (Reizer et al. 1996), Bacillus subtilis (Freymond et al. 2006) and Streptococci (Afzal et al. 2016). Not enough, however, is known about processes and genetical mechanisms underlying amino sugar metabolism to potentially use them in our advantage.
Metabolism of amino sugars comes in different ways, differing between bacterial species or even strains (Sadler et al. 1979; Brinkkötter et al. 2000; Ray and Larson 2004; Freymond et al. 2006; Leyn et al. 2012). Hence, a vast number of molecular mechanisms controlled by different operon and genes had been developed in the course of evolution. Because of that, at the moment, we are unable to see the whole picture of bacterial amino sugar metabolism (Shen et al. 2025). However, aga genes operon responsible for catabolism of such sugars, namely D-galactosamine (GalN) (Fig. 1A) and N-acety-D-galactosamine (GalNAc) (Fig. 1B) might serve as a good model for future investigations. This operon is widespread, especially in pathogenic bacteria.
The chemical structure of glycans. A-D-galactosamine (GalN), B-N-acety-D-galactosamine (GalNAc).
In many bacteria, such as E. coli, Enterobacter and Shewanella spp. an aga operon consists mostly of around twelve genes. This number, however, may vary due to other bacteria developing new genes, or adapting the genes responsible for other amino sugar catabolism (mainly Glucosamine) (Ray and Larson 2004; Leyn et al. 2012; Zhang et al. 2015). The characterization of aga genes as well as metabolic pathway controlled by proteins encoded by them are the subject of this article. We focused primarily on the mode of action, as well as the role of the aga genes in amino sugar metabolism. Finally, we rationalize why these pathways have a great potential as a target for therapy or diagnostics.
Both amino sugars are common components and build a variety of cell structures in both eukaryotic and prokaryotic domains. In bacteria, GalNAc is not only a component of the cell wall but is also found in lipopolysaccharide (LPS). For instance, Pseudomonas aeruginosa and Campylobacter jejuni both have GalNAc residuses in their LPS core, as well as require UDP-GalNAc in order to be able to build full length LPS molecule.(Masoud et al. 1995; Sadovskaya et al. 1998; Bernatchez et al. 2005). Some bacteria even use it to mimic our immune cells (De Jong et al. 2022). In mammals, it links carbohydrate chains in mucins (Carraway and Hull 1991). Both GalNAc and GalN are found in glycosylated proteins of both domains (Sadler et al. 1979; Abu-Qarn et al. 2008). Given these versatile roles we expect GalNAc/GalN metabolism to be closely linked to bacterial virulence (Zhang et al. 2015).
Such abundance and role of these amino sugars makes it no surprise that various mammalian pathogens use them to their advantage. For example, the amino sugars are known to be able to support the growth as carbon and nitrogen sources (Reizer et al. 1996). Brinkköter et al. presented in their study, that Wild-Type strains of E. coli, Klebsiella pneumoniae and Salmonella enterica Typhimurium could effectively use GalNAc and GalN as their main source of carbon and nitrogen. Compared to the laboratory strains, E. coli K-12, which only after some time developed mutations which allowed to use this metabolic pathway. These mutants had a phenotype suppressing the gat and nag genes responsible for galactitol and N-acetyl-D-glucosamine metabolism respectively. They could not however use GalN as their main source of carbon and nitrogen (Brinkkötter et al. 2000). This may suggest that an ability to utilize amino sugars is important for Wild-Type strains to maintain their virulence.
Another example of the usefulness of GalNAc for bacterial virulence may be the case of Camplylobacter jejuni, which can produce GalNAc-terminal Lipooligosacharides (LOS). These LOS can bind to the Macrophage Galactose-type lectin found on immature dendritic cells, which successfully mimics our immune system (De Jong et al. 2022).
The aga operon consists mainly of twelve genes encoding proteins serving various functions regarding GalNAc and GalN metabolism. However, as was already mentioned, there exist several orthologic groups of aga genes.
The catabolic pathway that uses GalNAc and GalN consists of five steps, as presented in Figure 2. Transport (1) of the substrates is realized by two PTS systems encoded by agaBCD and agaVWEF genes. Succeeded by the following phosphorylation by AgaK kinase to GalNAc-6-P and GalN-6-P respectively. Subsequent deacetylization (2) of GalNAc-6-P to GalN-6-P catalyzed by AgaA. Deamination and isomerization (3) of GalN-6-P (galactosamine-6-phosphate) by di-functional AgaS enzyme to tagatose-6-phosphate (Tag-6-P) which then undergoes another phosphorylation (4) catalyzed by AgaZ to tagatose-1,6-diphosphate (Tag-1,6-PP). The final step of this GalNAc pathway is Tag-1,6-PP cleavage, catalyzed by AgaY aldolase which leads to the production of glyceraldehyde-3-phosphate and glycerone phosphate (PEP) (Ray and Larson 2004; Leyn et al. 2012).
The catabolic pathway that uses GalNAc and GalN.
Interestingly, comparative genomics study by Leyn et al. suggested a vast diversity regarding the utilization of GalNAc/GalN pathway by Proteobacteria, such as Shewanella. This concerned especially the two first steps, with the latter three being more conserved (Leyn et al. 2012).
The aga genes in Proteobacteria are regulated by AgaR transcriptomal regulator from DeoR family of transcriptional factors, which recognizes specific sequences located in agaRZS promoter regions. Not only does it serve as an autoregulator but also negatively controls the expression of agaZ and agaS genes, binding to the specific palindromes preceding these genes (Ray and Larson 2004).
AgaR is a transcriptional regulator belonging to the DeoR family. Members of this family can be found in a variety of species, ranging from Gram-positive (Lactococcus lactis, Streptococcus mutans) to Gram-negative bacteria (E. coli, K. pneumoniae, P. aeruginosa), being present in around 58% of species of Prokaryota (Pérez-Rueda and Collado-Vides 2000; Ray and Larson 2004). E. coli family of DeoR regulators contains at least fourteen members, which usually function as repressors in sugar metabolism (Elgrably-Weiss et al. 2006). Examples being GutR (glucitol metabolism), LacR (lactose metabolism) FucR and FruR responsible for fucose and fructose respectively, as well as other (Pérez-Rueda and Collado-Vides 2000). Proteins in this family exhibit several common features with high degree of size conservation ranging from 240 to 260 amino acids and highly conserved regions, such as the second helix, known as recognition helix of the helix-turnhelix DNA-binding motif in the N-terminus. The first helix of the DNA-binding domain, however, presents little conservation(Pérez-Rueda and Collado-Vides 2000).
Recent studies by Zhang et al. and Leyn et al. show that there is at least five different orthologs of AgaR regulator characterized by different DNA motifs, discovered throughout 21 species of Proteobacteria, some of which even carrying two copies of agaR genes. Leyn et al. also observed strong tendencies for agaR genes to cluster on the chromosome with GalNAc utilization genes, which suggests conservation of AgaR function. All of the AgaR binding motifs, investigated by comparative genomics approach, shared a common CTTTC pattern with a common consensus of a direct repeat of this sequence. Groups (I), (II) and (III) shared a common CTTTC-5nt-CTTTC consensus, with the copy number and orientation differing between species. In contrast to that, group (IV) had an inverted repeat with the consensus CTTTC-15nt-GAAAG, while group (V) had a common structure with two inverted repeats GAAAG-(16-18)nt-GAAAG (Leyn et al. 2012).
Zhang et al., however, discovered only two, distantly relative, groups of AgaR (R1 and R2), sharing only 30% sequence similarity, as well as proposed different binding site motifs for these two orthologs. In most genomes analyzed using comparative genomics approach, they discovered that agaR1 had a tendency to cluster on a chromosome close with genes for glycoside hydrolase and PTS, while agaR2 has a similar tendency for co-localization with the genes encoding deacetylase, isomerase, and aldolase (Zhang et al. 2015). The candidate motifs for binding both regulators also shared a similar palindrome structure. AgaR1 binding sites had a length of 20 bp, whereas AgaR2 binding sites had 18bp. In addition, both AgaR binding motifs had an AT-rich central part with AgaR2-binding motif being more conserved and GC-rich in general (Zhang et al. 2015).
Typically, DeoR binding site is formed by the residues of several amino acids belonging to peripheral subdomains labeled P1 and P2 as well as a double Rossmann fold subdomain at their interface. Although the total sequence identity between different DeoR family regulators may differ even up to 80% difference, the three subdomains forming the binding site have a conservative structure, as well as position and ligand binding orientation (Škerlová et al. 2014). The effector molecule forms a strong covalent linkage with binding sites amino groups, deeply burring itself in the effector-binding site (Škerlová et al. 2014). Škerlová et al. also discovered that C-DeoR was the first discovered bacterial transcriptional regulator, that had its effector module covalently bound (Škerlová et al. 2014), suggesting there can be more DeoR family members expressing this characteristic.
During the study by Ray et al., two promoters for AgaR binding were discovered within agaR-agaZ region in E. coli K-12, as well as the third one in agaS-agaA intergenic region (Ray and Larson 2004). They also discovered that AgaR negatively regulates transcription from each of the three promoters. The absence of this repressor led to growthrate on galactosamine similar to that on glucose without the repressor. In addition to that, agaZ promoter was discovered to be a subject not only to repression by AgaR but also catabolite repression. Its expression was discovered to be 10 times higher in cells grown on casamino acids and GalN than on glucose without the functional AgaR. agaZ promoter region contained a sequence similar to that recognized by the cAMP-cAMP receptor protein (CRP) complex-(Zhang and Ebright 1990). In mutants with or without the functional agaR gene addition of cAMP resulted in 10-fold upregulation (Ray and Larson 2004).
The most conserved enzyme in GalNAc/GalN pathway discovered by Leyn et al. was AgaS, a hypothetical sugar phosphate isomerase from the SIS family, that was present in all analyzed genomes (Leyn et al. 2012). Enzymes belonging to this family are essential for bacterial proliferation, being often responsible for sugar catabolism, thus regulating general bacterial metabolism, allowing for biogenesis of virulence factors such as LPS, and modifying those factors (for instance altering the O-antigen sugar composition of LPS) as a mean of drug resistance (Gourlay et al. 2010).
The enzymes contain Sugar ISomerase (SIS) domain, responsible for sugar isomerization or sugar binding activities, yet differing with regards to their overall structure and sequences, sometimes even presenting less than 20% sequence similarity (Sommaruga et al. 2009; Gourlay et al. 2010).
Usually, SIS domain in enzymes has a catalytic function as isomerase and binds to phosphorylated sugars (Bateman 1999), in case of AgaS being GalN-6-P. The domain is also present in a family of bacterial transcriptional regulators, such as the ribose-phosphate-isomerase regulator RpiR, which regulates the rpiB gene (Sørensen and Hove-Jensen 1996). However, there are no reports of SIS domain regulators demonstrating catabolic activity yet (Bateman 1999).
The deaminase/isomerase activity of AgaS was evaluated by Leyn et al. based on the enzyme overexpressed in Shewanella. Its activity with GalN-6-P was approximately 27-fold higher than with GlcN-6-P (glucosamine-6-phosphate) (9,48 μmol/mg x min to 0,35 μmol/mg x min respectively). Their comparative genomic analysis also suggested that agaS is a universal catabolic gene in aga operon for all Proteobacteria. Unfortunately, at the moment of writing there is not much known about in vitro enzymatic activities of AgaS derived from other bacteria. Considering AgaS high conservatism, its high specificity towards galactosamine derivatives compared to other amino sugars, and the lack of in vitro research of this enzyme, it would be fair to state that, at the moment, enzymatic activity of AgaS isolated from Shewanella is representative of AgaS isomerases as a whole. In addition to that ΔagaS knockout mutants derived from Shewanella completely lost their ability to use GlcNAc as a sole carbon and nitrogen source in minimal medium. This deletion also potentially prevented the transcription of the following agaY gene. Therefore Leyn et al. confirmed AgaS to be essential in GlcNac/GalN catabolic pathway (Leyn et al. 2012), possibly inhibiting bacterial virulence.
AgaA performs the role of GalNAc-6-P deacetylase in this catabolic pathway. This enzyme functions as a catalyst for a bridge reaction of transforming N-acetyl-D-galactosamine-6-phosphate to D-galactosamine-6-phosphate. agaA gene is usually closely clustered with other aga genes. During their study Leyn et al. found two variants of AgaA enzyme, AgaAII being distinct, and characteristic only for Shewanella spp. A number 11 other species of Proteobacteria in which agaA gene has been found, had been functionally and genetically identical to that of E. coli. In Shewanella spp. AgaAII shared 50% of similarity to NagA, responsible for N-acetyl-D-glucosamine-6-phosphate (GlcNAc-6-P) deacetylation (Leyn et al. 2012).
Both variants of AgaA, as well as NagA belong to COG1820 protein family of amidohydrolases. Additional phylogenetic analysis by Leyn et al. has confirmed that AgaAII is a close paralog of NagA, which suggested that its development might have been a result of recent gene duplication event. Interestingly, in six Proteobacteria species analyzed by them, GalNAc-6-P deacetylases of both types were missing, suggesting that these organisms had the ability to utilize GalN, but not GalNAc (Leyn et al. 2012).
Thus, the presence or absence of agaA gene is crucial for the bacteria to utilize GalNAc. Leyn et al. as well as Zhang et al. have suggested that the presence of agaA, thus would also determine PTS transporters specificity (agaA lacking bacteria would have GalN-specific PTS), as was the case for Shewanella spp. as well as some other species (Leyn et al. 2012). As the result of their comparative genomics study Zhang et al. discovered one PTS previously described as GalN-specific in Lactobacillaceae. However, its co-occurrence and co-localization of its genes with agaA in most of the studied organisms was contrary to the previous suggestion (Zhang et al. 2015).
Additionally, Leyn et al. discovered the expression of agaAIIas well as agaK and agaS in Shewanella grown on GalNAc to be elevated over 100-fold compared to cells growing on GlcNAc (Leyn et al. 2012).
Enzymatic activity of AgaAII was also evaluated in the aforementioned study. The enzyme exhibited significantly higher deacetylase activity with GalNAc-6-P than with GlcNAc-6-P (7,98 μmol/mg x min to 0,76 μmol/mg x min respectively) (Leyn et al. 2012).
Further, E. coli K-12 strain had a large deletion of several aga genes as well as truncation of agaA, resulting in GalNAc-negative phenotype (Leyn et al. 2012).
AgaZ, which functions as Tag-6-P kinase, was present in most genomes studied by Leyn et al. in their comparative genomics study. Contrary to that, Zhang et al. discovered this enzyme and a gene encoding it throughout Lactobacillaceae. No paralogs of this enzyme were also found in genomes lacking them. However, it was suggested that this function is compensated by other enzymes, PfkA (phosphofructokinase I) and LacC, both having tagatose-6-phosphate activity (Leyn et al. 2012; Zhang et al. 2015). Brinkkötter et al. even suggesting that AgaZ functions as a non-catalytic subunit of AgaY [9,8].
Despite that, Leyn et al. observed in their study, that patterns of distribution of agaZ and agaY genes are different. This observation, as well as an upregulation of agaZ in GalNAc environment (see AgaR) (Ray and Larson 2004), however, does not support the previous hypothesis, and suggests that AgaZ has its essential role in GalNAc catabolism independent of AgaY, which has not been discovered. The Catabolic activity of AgaZ has not yet been studied and remains unknown.
AgaY is a tagatose-1,6-diphosphate aldolase, a final enzyme in GalNAc catabolic pathway, catalyzing Tag-1,6-PP breakdown to glycerone phosphate and D-glyceraldehyde-3-phosphate. It was found by Leyn et al. and Zhang et al. to be present in almost every member Enterobacterales and Vibrionales orders but missing in Shewanella and several other Proteobacteria (Leyn et al. 2012; Zhang et al. 2015). However, in Shewanella its activity is compensated by non-committed enzymes such as class II fructose-bisphosphate aldolase (Fba), present in all its species. Interestingly Fba in Shewanella spp. is more similar to AgaY than Fba in E. coli (50% to 35% sequence similarity) (Leyn et al. 2012). Moreover, Haemophilus parasuis, pathogenic bacteria which cause Glasser disease in pigs, had a unique variant of GalNAc utilization genes including: a different agaYII type, encoding an alternative version of tagatose-1,6-biphosphate aldolase belonging to LacC family (Rosey et al. 1991), as well as a unique type V PTS (Leyn et al. 2012).
It is worth mentioning that during their study in Shewanella spp. Leyn et al. discovered that the deletion of agaS gene prevented agaY from expression, thus resulting in a mutant’s inability to use GalNAc. Complementation of this effect via restoring both agaS and agaY resulted in restoration of this ability, which was not the case when only one of them was complemented (Leyn et al. 2012).
agaBCD and agaVWEF from the AgaR regulon encode two types of phosphotransferase (PTS) systems. Complex enzyme systems widely used by bacteria for the detection, transport and phosphorylation of various sugar substrates, including monosaccharides, disaccharides, amino sugars, polyols, and other sugar derivatives (Sørensen and Hove-Jensen 1996; Leyn et al. 2012). PTS systems catalyze the uptake of carbohydrates as well as their conversion to their respective phosphoesters during transport. The source of energy for these systems is phosphoenolpyruvate or PEP. The PTS systems have two general components: Histidine Phosphocarrier protein (HPr) with enzyme I and membrane bound sugar specific permeases (Enzymes II). Each enzyme II consists of one or two hydrophobic and two hydrophilic domains. They can exist as distinct proteins, as well as a single multidomain protein. Catalysis of the uptake of sugars and their conversion to phosphoestre is performed by four successive phosphoryl transfers. Initial phosphorylation of enzyme I using PEP as a substrate, transfer of the phosphoryl group from enzyme I to HPr, the self-phosphoryl transfer in HPr catalyzed by enzyme II, after which the phosphoryl group is transferred to histidine or cysteine residues of enzyme II. The sugar is transported through the membrane-bound enzyme II and undergoes phosphorylation (Meadow et al. 1990; Hassan et al. 2014).
PTSIIGalNAc (agaBCD) being GalN-specific and GalNAc-specific PTSIIGalN (agaVWEF) (Reizer et al. 1996; Ray and Larson 2004; Leyn et al. 2012). Both systems belong to the mannose-sorbose family (Leyn et al. 2012). PTSII contains three domains (IIB, IIC and IID) encoded by the three aga genes, which are fused to one peptide. agaF however, encodes IIA PTS protein, that functions in the transport of both amino sugars (Ray and Larson 2004). During their study Leyn et al. discovered four types of PTS in Proteobacteria and distinguished two separate clades of PTS based on the components that are encoded by gene loci containing the adjacent agaA deacetylase gene. This may hint that these two clades (labeled PTSI and PTSIII) are GalNAc-specific, whereas PTS components not encoded in close vicinity to agaA (PTSII and PTSIV), are GalN-specific (Leyn et al. 2012). Zhang et al. discovered a separate uncharacterized PTSV type system which is found in some Proteobacteria (Zhang et al., 2015).
Amino sugar specific PTS play a crucial role of defining bacterial ability of their utilizations. Bacteria without them, for example, E. coli K-12 strain which lacks GalNAc-specific PTS, cannot use this sugar as a sole carbon, nor nitrogen source like other Proteobacteria (Brinkkötter et al. 2000; Mukherjee et al. 2008; Leyn et al. 2012). Some bacteria, however, without this specific PTS systems, for example Shewanella, developed unique sets of GalNAc- and GalN-specific permeases (AgaP) and kinases (AgaK) (Leyn et al. 2012).
AgaP is an amino sugar transporter protein, which is commonly accompanied by other amino sugar related transporters belonging to Ton-B-dependent receptors. Shewanella spp., as well as Burkholderia cenocepacia and Caulobacter spp., which lacks typical GalNAc-specific transporters utilizes sugar uptake through the outer membrane using a TonB-dependent OmpAga transporter. Transport through the inner membrane is done by AgaP permease. The subsequent phosphorylation of amino sugar is performed by AgaK kinase (Leyn et al. 2012).
AgaP was found to be a close paralog (50% similarity) to NagP, a GlcNAc permease belonging to GGP sugar transporter family (Rodionov et al. 2010; Leyn et al. 2012). AgaK was found by Leyn et al. to be most similar to the Shewanella spp. GlkII glucokinase belonging to ROK family (35% similarity) (Rodionov et al. 2010; Leyn et al. 2012).
The aga cluster genes in Burkholderia cenocepacia and Caulobacter encoded different AgaPII and AgaKII variants (belonging to EamA and BcrAD_BadFG families respectively). With the absence of GalNAc-6-P deacetylase, and GalNAc-, GalN-specific PTS in their genomes, it was suggested that these enzymes are involved in GalN uptake and phosphorylation (Leyn et al. 2012).
This hints at the importance of GalNAc utilization for bacteria, which develop alternative routes of its uptake if the classic aga-controlled pathway is unavailable.
Another important aspect of amino sugar metabolism is its practical use by pathogenic bacteria that can be turned to our advantage. As was mentioned earlier, both amino sugars are directly or indirectly connected to bacterial virulence factors, examples being: LPS, murein and protein glycosylation and in some cases molecular mimicry. At the moment, however, there is not much knowledge available, with the exception of a few case and genomic studies, about how GalNAc and GalN utilization influences bacterial virulence.
The example of a case study is one conducted by Mukherjee et al. on several E. coli O157:H7 strain isolates derived from 2006 spinach outbreak compared to other E. coli strain notably K-12. They discovered that most of the spinach-associated O157:H7 isolates presented similar to K-12 strain GalNAc- phenotype unlike most of the other available O157:H7 representatives. It was suggested that this change was a result of a neutral mutation in agaF gene responsible for encoding Enzyme II of GalNAc-specific PTS. The aforementioned mutation has had a tendency to spread among E. coli O157:H7 as an adaptation useful in colonizing new niches (Mukherjee et al. 2008). This hints at the fact that one of the reasons E. coli K-12, (in case of the other strains, a widely spread multi-niche pathogen) is unable to secure a successful infection to be a result of its inability to use amino sugars, represented by GalNAc, as a carbon and nitrogen source highly present in animal and human organisms. Knowing this may help us understand strain-specific pathogenicity and perhaps even combat it.
Confirming the previous statement, Zhang et al. in their study conducted several Proteobacterial invasion assays based on animal models, and discovered that in case of Streptococcus suis, mostly a cattle-based pathogen with a limited ability to transfer and cause infection in humans, GalNAc/GalN utilization regulated by AgaR2 played a crucial role in its virulence (Zhang et al., 2015).
In the same study authors went as far as to suggest that both amino sugars took part in bacterial recognition and crosstalk, thus through maintenance and regulation of their utilization pathway allowing for successful infections (Zhang et al. 2015).
On the other hand, for Proteus mirabilis, a mostly human pathogen responsible for Urinary Tract Infections (mostly catheter-associated urinary tract infections, CAUTIs), but sometimes appearing in veterinary conditions, usage of amino sugars via aga genes also seemed to be important. As a result of a genome-wide transposon mutagenesis of Armbruster et al. AgaR regulator was listed as one of the fitness factors for human kidney colonization in this uropathogenic bacteria (Armbruster et al. 2017). However, the exact role and extent of GalN/GalNAc metabolisms influence on uropathogenicity is yet to be investigated.
How will this knowledge allow us to specifically combat pathogen strains which base their pathogenicity on the ability to use amino sugars? This would be possible through targeting key pathway elements in their metabolism, or bacterial constructs using such sugars similarly to as discovered by Gill et al. during their study. According to them GalNAc-linked post-translational modifications were used by pathogenic bacteria to modify host GTPases, through toxins, with α-GalNAc-O-Tyr in order to promote their virulence (Gill et al. 2011). Based on this information Behren et al. prepared vaccine constructs as well as polyclonal antibodies specific to this modification. They suggested that GalNAc protein residues might become a vital target in specific glycoproteomal detection, as well as vaccines and therapy in the future (Behren et al. 2023).
Not much is still known about amino sugars, represented by N-acetyl-d-galactosamine and D-galactosamine, role in bacterial pathogenicity. Recent studies, however, show that human and animal pathogens, able to successfully secure infections, developed highly sophisticated and specific processes of their utilization, especially in comparison to non-pathogens who often lack the ability (Shen et al. 2025). Amino sugars utilization often appears alongside other, already known to be important, virulence factors is sure to be directly or indirectly involved in developing bacterial pathogenicity. Hence, it is not to our surprise that there are more and more real possibilities for these amino sugars, their utilization pathways as well as the aga operon responsible for it, to be used as targets in bacterial classification, pathogen detection and possibly even therapy start to appear. To achieve this, however, more studies regarding GalNAc/GalN utilization pathway in bacteria should be conducted in the future.