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PubMed2026

Comprehensive in silico genomics analysis of global trends and host-specific emergence of aminoglycoside resistance in Staphylococcus aureus: a One-Health perspective.

BACKGROUND: Aminoglycosides remain clinically valuable against Staphylococcus aureus. Aminoglycoside resistance in S. aureus represents a critical One Health concern and is primarily driven by aminoglycoside-modifying enzymes (AMEs), which are frequently plasmid-encoded. Although regional studies have provided valuable insights, the global epidemiology of aminoglycoside resistance determinants remains poorly characterized because comprehensive data integrating human, animal, and environmental reservoirs are still lacking. This study addresses this gap by analyzing over 110,000 S. aureus genomes (2000-2025) to map the global resistome, quantify temporal and host-specific trends, and assess the association between genetic determinants and phenotypic resistance. METHODS: We performed a retrospective One Health meta-analysis of 110,309 S. aureus genomes collected between 2000 and 2025 from 128 countries. Genomes were quality-filtered and aminoglycoside resistance determinants were identified using NCBI AMRFinderPlus (v4.0.23). Multilocus sequence typing and host-source harmonization (Human, Animal, Environment, Unknown) enabled clonal and reservoir stratification. Temporal trends in gene prevalence and resistance burden were modeled with robust regression. Geographic and host-associated structuring of key genes was assessed via &#x3c7;2 and enrichment tests. Machine-learning models (elastic-net, random forests, XGBoost) were benchmarked for minimum inhibitory concentration (MIC) prediction via nested cross-validation, with performance evaluated by mean absolute error, RMSE, and SHAP-based feature importance. All analyses were conducted in R and Python using publicly available, de-identified genomic data. RESULTS: Aminoglycoside resistance-associated genes were dominated by modifying enzyme determinants, with ant(6)-Ia, ant(9)-Ia, aph(3')-IIIa, sat4, aadD1, and aac(6')-Ie/aph(2'')-Ia occurring in 14-22% of isolates worldwide. Temporal analysis revealed significant declines in several major determinants, most notably ant(9)-Ia (-2.22 percentage points per year, p&#x2009;<&#x2009;0.001), whereas apmA exhibited a non-significant decreasing trend in animal isolates. Host structuring was marked: human clinical isolates concentrated common determinants, while animal and environmental isolates harbored rare alleles (apmA, spw, str, spd). Geographic mapping confirmed near-universal distribution of common genes but focal restriction of rare ones. Publicly available phenotypic data indicated strong activity of amikacin, whereas gentamicin showed a distinct resistant subpopulation that closely corresponded with AME gene carriage. Genotype-phenotype analyses demonstrated strong concordance, with gene-rich complements predicting resistant MIC strata and absence of determinants predicting susceptibility. Analysis across different gene classes revealed frequent co-occurrence of aminoglycoside resistance genes with determinants from other classes, such as mecA, blaZ, and MLS_B, embedding them within multidrug-resistant (MDR) genomic contexts. CONCLUSION: Over 25&#xa0;years, the prevalence of aminoglycoside resistance-associated genes in S. aureus has declined for several common determinants, while rare veterinary-linked alleles are emerging in animal isolates. Strong genotype-phenotype concordance supports genomic prediction for gentamicin and amikacin, where MIC data are available, although phenotypic confirmation remains essential. The frequent co-occurrence of aminoglycoside resistance genes with other antimicrobial resistance determinants indicates their integration within co-occurrence patterns of MDR genes, defined here as clusters of co-occurring resistance genes often carried on shared mobile genetic elements. These patterns highlight the need for integrated One Health surveillance combining clinical, veterinary, and environmental monitoring with plasmid-context resolution to anticipate emerging threats.

Aminoglycosides↗
PubMed1976

Multiple-aminoglycoside-resistant mutants of Bacillus subtilis deficient in accumulation of kanamycin.

Three classes of spontaneous multiple-aminoglycoside-resistant (mar) mutants of Bacillus subtilis were isolated by plating on a low (1.2 mug/ml) concentration of kanamycin sulfate and were found to be resistant also to low concentrations of paromomycin, neomycin and gentamicin. The three classes could be distinguished one from another by their degree of cytochrome deficiency, respiration deficiency, and susceptibility to kanamycin lethality. A fluctuation test showed that the mutations were spontaneous and not induced by the conditions of selection. Representative strains from two classes of mutants (mar-2 and mar-3) accumulated aminoglycoside very poorly in comparison with the parent strain, whereas a strain of the third class (mar-1) inactivated aminoglycoside present in the growth medium. The mar-3 strain studied (aroD163) had previously been shown to be a menaquinone auxotroph (Farrand and Taber, 1973) and to be deficient in amino acid uptake (Bisschop et al., 1975). Such mutants, which are resistant to low concentrations of aminoglycosides, may be of use in elucidating the biochemical and genetic bases of certain bacterial transport systems.

Aminoglycosides↗
PubMed1979

Clinical isolation and characterization of aminoglycoside-resistant small colony variants of Enterobacter aerogenes.

Small colony variants of Enterobacter aerogenes, as well as the parental large colony type, grew in blood drawn for cultures on three separate days from a patient who had received suboptimal gentamicin therapy. Minimum inhibitory concentrations of four aminoglycoside antibiotics were eight to more than 16 times higher for small colony variants than for the normal large colony type. Small colony variants had defective catalase activity, which may have interfered with oxidative metabolism and aminoglycoside uptake. Small colony variants reverted readily to the parental type in vitro in the absence of aminoglycosides. Clinically isolated small colony variants appeared similar to those selected in the presence of gentamicin in vitro, with respect to colony morphology, aminoglycoside resistance and catalase deficiency. The isolation of small colony variants during gentamicin therapy in vivo suggests that such variants may be a cause of treatment failure in patients receiving aminoglycosides.

Aminoglycosides↗
PubMed1979

Aminoglycoside-modifying enzymes among clinical isolates of Acinetobacter calcoaceticus subsp. anitratus (Herellea vaginicola): explanation for high-level aminoglycoside resistance.

Acinetobacter calcoaceticus subsp. anitratus (Herellea vaginicola) is an important cause of nosocomial infection in our hospital where A. calcoaceticus subsp. anitratus is the most frequently isolated gram-negative species resistant to one or more of the aminoglycoside antibiotics. Of 167 strains tested for susceptibility to aminoglycosides, only 6 strains were found that were resistant to >/=128 mug of kanamycin per ml; all others were susceptible to </=32 mug/ml. Five of these six strains were found to produce aminoglycoside-modifying enzymes. Two strains produced a phosphotransferase which mediates resistance to kanamycin and neomycin; three strains produced an acetyltransferase which mediates resistance to kanamycin, tobramycin, and amikacin (minimal inhibitory concentration >/= 128 mug/ml for each drug). No strain with lower level resistance to kanamycin, tobramycin, or amikacin had enzyme activity. Fourteen strains resistant to gentamicin failed to show significant enzymatic modification of that antibiotic. Although agarose gel electrophoresis of deoxyribonucleic acid preparations from the enzyme-producing strains showed plasmid bands in all, no transfer of aminoglycoside resistance could be achieved, nor was it cured by exposure to novobiocin, ethidium bromide, acridine orange, heat, or prolonged storage. Resistance to mercuric chloride, present in 2 of 60 strains, was lost by 1 strain after exposure to novobiocin, and the loss of resistance was associated with an apparent deletion of plasmid deoxyribonucleic acid.

Acinetobacter↗
PubMed1976

Suceptibility of aminoglycoside-resistant gram-negative bacilli to amikacin: delineation of individual resistance patterns.

Gram-negative bacilli isolated from clinical specimens submitted for culture in two Paris hospitals during 1974 were studied for susceptibility to six currently used aminoglycosides: kanamycin, neomycin, paromomycin, lividomycin, gentamicin, and tobramycin. Resistance patterns of strains of various species including those of Enterobacteriaceae, Pseudomonas, and Moraxella were determined, and the strains were grouped into eight resistance "phenotypes." In comparative studies of 807 strains belonging to different phenotypes, amikacin was markedly more active than any of the six other antibiotics; at concentrations of less than or equal to 4 mug/ml, it inhibited about 88% of the strains, including those resistant to gentamicin and tobramycin. Some amikacin-resistant strains were found among different species. The mechanism of resistance to amikacin of strains of Serratia and Moraxella group II was related to an N-acetylating enzyme. Amikacin can be expected to be useful as an alternative treatment of infections due to gram-negative bacilli sensitive to aminoglycosides and also, more particularly, for the treatment of patients infected with multiresistant strains.

Amikacin↗
PubMed1977

Aminoglycoside-resistant enterococci.

Thirty-four recent clinical isolates of Streptococcus faecalis were tested for sensitivity to amoxycillin, benzylpenicillin, streptomycin, kanamycin, gentamicin, tobramycin, and amikacin. Amoxycillin was two- to four-fold more active than benzylpenicillin and all strains were inhibited by low concentrations of the penicillins. The aminoglycosides were less active against the enterococci than were the penicillins and a significant number of strains were insensitive or relatively insensitive to one or more of the aminoglycosides. Thus, eight (23%) strains showed a high level of resistance to streptomycin and kanamycin (MIC greater 5000 microng/ml) but were sensitive to gentamicin, tobramycin, and amikacin. In addition, two strains of Strep. faecalis, isolated at different hospitals from patients who had received topical gentamicin therapy, were relatively resistant to gentamicin (MIC250 to 500 microng/ml) and were less sensitive also to the other aminoglycosides. Bactericidal synergy was demonstrated by amoxycillin/aminoglycoside combinations against the enterococci, provided that the test strain of Strep. faecalis was sensitive to the aminoglycoside in the combination. An exception to this was the combination of amoxycillin plus amikacin which was not synergistic against kanamycin-resistant strains of Strep. faecalis although these organisms were sensitive to amikacin in the growth inhibition tests. The gentamicin-resistant strains showed variable responses to amoxycillin/aminoglycoside combinations in tests for bactericidal synergy and were generally less sensitive than typical strains of Strep. faecalis.

Aminoglycosides↗
PubMed1978

Effect of enzymatic adenylylation on dihydrostreptomycin accumulation in Escherichia coli carrying an R-factor: model explaining aminoglycoside resistance by inactivating mechanisms.

Strains of Escherichia coli carrying R-factor R71(a), which codes for a streptomycin-spectinomycin adenylyltransferase, have elevated levels of resistance to dihydrostreptomycin (DHS) compared with isogenic R(-) bacteria. DHS accumulated by whole cells and spheroplasts of R(+) bacteria is lower than that observed for R(-) strains, a result of the absence of the second and more rapid of the two energy-dependent phases of DHS uptake seen in susceptible E. coli. A mutant of R(+)E. coli with reduced DHS resistance has been shown to have reduced levels of streptomycin-spectinomycin adenylyltransferase activity as well as enhanced drug accumulation. Actively accumulated DHS was recovered from R(+) cells as the adenylylated derivative. Neither was inactivated antibiotic detected in culture filtrates, nor was actively accumulated drug lost from R(+) cells under normal conditions. The cellular distribution of actively accumulated DHS in R(+) and R(-) cells was found to be the same. Membranes isolated from these cells retained only a small fraction ( approximately 1%) of the total cell-associated drug. The R(+) derivative of a mutant with defective energy transduction (E. coli NR-70) and reduced ability to transport aminoglycosides has a significantly higher minimal inhibitory concentration of DHS than its R(+) parent (strain 7). Streptomycin-spectinomycin adenylyltransferase activity, from comparisons of K(m) values and total activities of enzyme, was the same in both strains. The enzyme has been localized to the exterior surface of the bacterial inner membrane, although isolated membranes lacked detectable enzyme activity. The preceding observations are consistent with the proposal that the level of R71(a)-mediated DHS resistance is the outcome of competition between the rate of adenylylation and the rate of the first energy-dependent phase of DHS transport. When the rate of adenylylation exceeds the first energy-dependent phase, adenylylated DHS is accumulated, apparently in a manner identical to the accumulation of DHS. Unlike DHS, adenylylated DHS does not interact with ribosomes, and, consequently, there is a failure to initiate ribosomally dependent sequelae such as the second energy-dependent phase of accumulation, inhibition of protein synthesis, and/or misreading of mRNA.

Aminoglycosides↗
PubMed1977

Mechanisms of resistance to aminoglycosides.

Bacterial resistance to aminoglycoside antibiotics occurs by a variety of mechanisms. In clinical situations the most common mechanism is plasmid-determined modification of the drug that leads to a block of transport of the antibiotic into the cell. Amikacin, a semisynthetic aminoglycoside, is effective against a number of resistant strains because it has fewer sites of modification.

Amikacin↗
PubMed1979

Mechanism of aminoglycoside antibiotic resistance in anaerobic bacteria: Clostridium perfringens and Bacteroides fragilis.

Cell-free amino acid incorporation using ribosomes from strains of either Clostridium perfringens or Bacteroides fragilis was shown to be susceptible to inhibition by streptomycin and gentamicin. Ribosomes bound dihydrostreptomycin as effectively as ribosomes from Escherichia coli. No inactivation of streptomycin or gentamicin was detected by cell extracts of either anaerobic bacterial species. B. fragilis, grown without added hemin, menadione, and fumarate, and C. perfringens did not show any time-dependent accumulation of dihydrostreptomycin or gentamicin at concentrations tested. Decreased resistance to aminoglycosides and time-dependent uptake of dihydrostreptomycin at 500 mug/ml was observed with B. fragilis grown with hemin, menadione, and fumarate. With the last additions, cytochrome b was detected by cytochrome spectra of B. fragilis. These results demonstrate that anaerobic bacteria unable to carry out oxygen- or nitrate-dependent electron transport are resistant to streptomycin and gentamicin because of failure to transport aminoglycosides. The induction of fumarate-dependent electron transport in B. fragilis is associated with some aminoglycoside transport that is of poor efficiency relative to bacteria with electron transport to oxygen or nitrate.

Anaerobiosis↗
PubMed1975

R factor-mediated aminoglycoside antibiotic resistance in Pseudomonas aeruginosa: a new aminoglycoside 6'-N-acetyltransferase.

The newly introduced semisynthetic aminoglycoside antibiotics, i.e., 3',4'-dideoxykanamycin B (DKB), 6'-N-methyl DKB (6'-Me-DKB) and amikacin (AK) have been found to be effective against gram-negative pathogens including Pseudomonas aeruginosa, which are resistant to the known aminoglycoside antibiotics. We have demonstrated in our stock cultures two types of P. aeruginosa strains resistant to DKB, i.e., (DKB(r).AK(r).6'-Me-DKB(s)) and (DKB(r).AK(s).6'-Me-DKB(r)) (where r = resistant; s = sensitive). Both groups of strains inactivate the drugs by acetylation. The acetylating enzyme was extracted from GN4925(DKB(r).AK(s).6'-Me-DKB(r)) and purified by affinity chromatography. Enzymatic studies of the inactivation reaction and chemical studies of the inactivated products indicated that DKB and 6'-Me-DKB were inactivated by acetylation of the 6'-amino group of the drugs. This enzyme acetylates kanamycin A (KM-A), KM-B, DKB, 6'-Me-DKB, 6'-N-methyl kanamycin B, but not KM-C, AK, and gentamicin C(1). The enzyme is named aminoglycoside 6'-N-acetyltransferase 3. Genetic studies of two strains resistant to DKB and 6'-Me-DKB disclosed that the enzyme catalyzing inactivation of both DKB and 6'-Me-DKB was mediated by an R factor, i.e., R(ms167) and R(ms168), capable of conferring resistance to KM, DKB, and 6'-Me-DKB, in addition to resistance to gentamicin, streptomycin, and sulfanilamide, and resistance to tetracycline, chloramphenicol, streptomycin and sulfanilamide respectively.

Acetyltransferases↗
PubMed1978

Mutations determining generalized resistance to aminoglycoside antibiotics in Escherichia coli.

Mutations conferring resistance to low levels of kanamycin in Escherichia coli have been mapped at 3 locations: the unc locus (min. 83), a locus we have designated kanA (MIN. 72), close to strA (rpsL), and a locus at min. 86.5 previously discovered by Plate (1976) that we have designated ecfB. The unc and ecfB mutations are associated with defects in energy metabolism, while mutations at kanA may be in the gene coding for ribosomal protein S12 (rpsL). The three types of mutations cause cross resistance to a number of different aminoglycoside antibiotics and the effects of the mutations are cumulative in combination.

Ampicillin↗
PubMed2025

Global genomic and antimicrobial resistance profiling of Neisseria gonorrhoeae: Insights from whole genome sequencing and minimum inhibitory concentration analysis.

BACKGROUND: The rising antimicrobial resistance (AMR) of Neisseria gonorrhoeae is a major global health concern that limits treatment options and complicates disease management. Efflux pump systems and resistance genes are key to bacteria's ability to evade antibiotics. This study examined the genetic and phenotypic resistance landscape using a large dataset of whole-genome sequences to identify key resistance mechanisms, assess efflux pump gene prevalence, and analyze regional variations in Minimum Inhibitory Concentration (MIC) values to inform treatment strategies and public health interventions. METHODS: A total of 38,585 whole-genome sequences of N. gonorrhoeae were analyzed to identify AMR determinants. This study focused on the presence and distribution of efflux pump genes (mtrC, farB, norM, and mtrA) and specific resistance genes, including tet(C) (tetracycline resistance) and aph(3')-Ia (aminoglycoside resistance). The MIC values were assessed for multiple antibiotics to evaluate resistance trends and regional variations, including penicillin, spectinomycin, zoliflodacin, gentamicin, and fluoroquinolones. RESULTS: This analysis revealed widespread resistance to multiple antibiotics. Efflux pump genes (mtrC, farB, norM, and mtrA) were found in nearly all isolates, highlighting their essential roles in resistance and adaptation. The presence of tet(C) and aph (3')-Ia varied across different Gene Presence Patterns, suggesting that regional or therapeutic factors may influence tetracycline and aminoglycoside resistance. High MIC values for penicillin were observed, likely because of blaTEM, a beta-lactamase gene responsible for beta-lactam resistance. Resistance to spectinomycin is also widespread, raising concerns about the diminishing efficacy of this antibiotic. In contrast, zoliflodacin, gentamicin, and fluoroquinolones exhibited relatively low MIC values, indicating their sustained effectiveness against N. gonorrhoeae. DISCUSSION: Efflux pump systems are key to N. gonorrhoeae resistance and adaptability. Regional MIC variations indicate that local antibiotic use shapes resistance patterns. The high resistance to penicillin and spectinomycin highlights the need for alternative treatments, whereas zoliflodacin and fluoroquinolones remain effective but require monitoring. This study emphasizes global AMR surveillance, novel therapies, and targeted antimicrobial stewardship to address multidrug-resistant infections.

Neisseria gonorrhoeae↗