About

M.-N. Frances Yap is a Principal Investigator at the Northwestern University Feinberg School of Medicine, associated with the Yap Laboratory. She holds a PhD from the University of Wisconsin-Madison. Her research focuses on microbiology and immunology, contributing to the understanding of biological processes through her laboratory's investigations. The laboratory includes a diverse team of research associates, postdoctoral fellows, students, and interns, all working under her guidance to advance scientific knowledge in her field.

Research topics

• Cell biology
• Biochemistry
• Biology
• Chemistry
• Genetics

Selected publications

• Inactivation of a purine biosynthesis repressor promotes ribosome synthesis to overcome antibiotic stress

  mBio · 2026-04-13

  articleOpen accessSenior author

  ABSTRACT Macrolide, lincosamide, and streptogramin (MLS) antibiotics are structurally distinct molecules that inhibit protein synthesis by binding overlapping sites within the 23S rRNA of bacterial ribosomes. The clinical utility of MLS antibiotics has diminished due to the dissemination of e rythromycin r esistance rRNA m ethyltransferase (Erm) genes. Staphylococcus aureus ErmB methylates the universally conserved A2058 nucleotide of the 23S rRNA (m 6 A2058), resulting in cross-resistance to all MLS antibiotics by reducing drug-binding affinity. The operonic upstream ribosome stalling peptide ErmBL was thought to be the sole regulatory element controlling ErmB synthesis and the extent of MLS resistance. Unexpectedly, our laboratory evolution experiments revealed that numerous loss-of-function mutations outside the bicistronic ermBL-ermB operon amplify ErmB-mediated MLS resistance. Among these are mutations in genes critical for purine de novo biosynthesis and the salvage pathway. Specifically, inactivation of the gene encoding the purine biosynthesis transcriptional repressor (PurR) converts an otherwise moderately resistant ermBL-ermB (ermB + ) strain into one exhibiting pronounced hyper-resistance to MLS antibiotics. This cooperative resistance phenotype is not attributable to increased ermB expression or elevated m 6 A2058 modification. Instead, purR inactivation leads to derepression of purine and pyrimidine biosynthesis, accompanied by increased expression of ribosome components. We find that the elevated ribosome abundance and translational capacity of the ermB + ∆ purR are directly proportional to its accelerated growth rate, thereby priming S. aureus for survival under high MLS concentrations. These findings support a model in which expanded nucleotide metabolites and a surplus of antibiotic-free ribosomes drive global translation to buffer the inhibitory effects of MLS antibiotics. IMPORTANCE The Erm rRNA methyltransferase superfamily represents the most prevalent determinant of MLS resistance in nosocomial Gram-negative and Gram-positive bacteria. Previous studies have established that erm expression is primarily governed by upstream ribosome stalling peptide and the 5′ untranslated regions. Using the widespread S. aureus ermBL-ermB ( ermB + ) operon as a model system, we unexpectedly identified second-site mutations in purR that synergistically enhance MLS resistance in an ermB + background. Loss of purR function derepresses nucleotide biosynthesis and ribosome production, thereby promoting bacterial growth under antibiotic stress. While numerous purR single-nucleotide polymorphisms across multiple species have been associated with antibiotic resistance, no study has directly linked these sequence polymorphisms to their regulatory function. Our results highlight the critical role of ribosome abundance and nucleotide metabolism in shaping antibiotic efficacy.

  PublisherDOI

• Abstract 1776 Machine learning-based classification reveals distinct clusters of non-coding genomic allelic variations associated with Erm-mediated antibiotic resistance

  Journal of Biological Chemistry · 2025-05-01

  articleOpen access

  The erythromycin resistance RNA methyltransferase (erm) confers cross-resistance to all therapeutically important macrolides, lincosamides, and streptogramins (MLS phenotype). The expression of erm is often induced by the macrolide-mediated ribosome stalling in the upstream co-transcribed leader sequence, thereby triggering a conformational switch of the intergenic RNA hairpins to allow the translational initiation of erm. We investigated the evolutionary emergence of the upstream erm regulatory elements and the impact of allelic variation on erm expression and the MLS phenotype.

  PublisherOA PDFDOI

• A promiscuous Bcd amino acid dehydrogenase promotes biofilm development in Bacillus subtilis

  npj Biofilms and Microbiomes · 2025-06-21 · 4 citations

  articleOpen accessSenior author

  Glutamate dehydrogenase (GDH) resides at the crossroads of nitrogen and carbon metabolism, catalyzing the reversible conversion of L-glutamate to α-ketoglutarate and ammonium. GDH paralogs are ubiquitous across most species, presumably enabling functional specialization and genetic compensation in response to diverse conditions. Staphylococcus aureus harbors a single housekeeping GDH (GudB), whereas Bacillus subtilis encodes both a major and a minor GDH, GudB and RocG, respectively. In an unsuccessful attempt to identify an alternative GDH in S. aureus, we serendipitously discovered previously unrecognized GDH activity in two metabolic enzymes of B. subtilis. The hexameric Val/Leu/Ile dehydrogenase Bcd (formerly YqiT) catabolizes branched-chain amino acids and to a lesser extent glutamate using NAD+ as a cofactor. Removal of gudB and rocG unmasks the dual NAD(P)+-dependent GDH activity of RocA, which otherwise functions as a 3-hydroxy-1-pyrroline-5-carboxylate dehydrogenase. Bcd homologs are prevalent in free-living and obligate bacteria but are absent in most, if not all, staphylococci. Despite low sequence homology, Bcd structurally resembles the GudB/RocG family and can functionally compensate for the loss of GudB in S. aureus. Bcd is essential for the full maturation of biofilms. B. subtilis lacking GDHs exhibits severe impairments in rugose architecture and colony expansion of biofilms. This study underscores the importance of metabolic redundancy and highlights the critical role of substrate promiscuity in GDHs during biofilm development.

  PublisherOA PDFDOI

• Structural studies on ribosomes of differentially macrolide-resistant<i>Staphylococcus aureus</i>strains

  Life Science Alliance · 2025-06-09 · 1 citations

  articleOpen access

  Antimicrobial resistance is a major global health challenge, diminishing the efficacy of many antibiotics, including macrolides. In Staphylococcus aureus , an opportunistic pathogen, macrolide resistance is primarily mediated by Erm-family methyltransferases, which mono- or dimethylate A2058 in the 23S ribosomal RNA, reducing drug binding. Although macrolide–ribosome interactions have been characterized in nonpathogenic species, their structural basis in clinically relevant pathogens remains limited. In this study, we investigate the impact of ermB -mediated resistance on drug binding by analyzing ribosomes from S. aureus strains with varying levels of ermB expression and activity. Using cryo-electron microscopy, we determined the high-resolution structures of solithromycin-bound ribosomes, including those with dimethylated A2058. Our structural analysis reveals the specific interactions that enable solithromycin binding despite double methylation and resistance, as corroborated by microbiological and biochemical data, suggesting that further optimization of ketolide–ribosome interactions could enhance macrolide efficacy against resistant S. aureus strains.

  PublisherOA PDFDOI

• Machine learning-based classification reveals distinct clusters of non-coding genomic allelic variations associated with Erm-mediated antibiotic resistance

  mSystems · 2024-07-02 · 4 citations

  articleOpen access

  ABSTRACT The erythromycin resistance RNA methyltransferase ( erm ) confers cross-resistance to all therapeutically important macrolides, lincosamides, and streptogramins (MLS phenotype). The expression of erm is often induced by the macrolide-mediated ribosome stalling in the upstream co-transcribed leader sequence, thereby triggering a conformational switch of the intergenic RNA hairpins to allow the translational initiation of erm . We investigated the evolutionary emergence of the upstream erm regulatory elements and the impact of allelic variation on erm expression and the MLS phenotype. Through systematic profiling of the upstream regulatory sequences across all known erm operons, we observed that specific erm subfamilies, such as ermB and ermC , have independently evolved distinct configurations of small upstream ORFs and palindromic repeats. A population-wide genomic analysis of the upstream ermB regions revealed substantial non-random allelic variation at numerous positions. Utilizing machine learning-based classification coupled with RNA structure modeling, we found that many alleles cooperatively influence the stability of alternative RNA hairpin structures formed by the palindromic repeats, which, in turn, affects the inducibility of ermB expression and MLS phenotypes. Subsequent experimental validation of 11 randomly selected variants demonstrated an impressive 91% accuracy in predicting MLS phenotypes. Furthermore, we uncovered a mixed distribution of MLS-sensitive and MLS-resistant ermB loci within the evolutionary tree, indicating repeated and independent evolution of MLS resistance. Taken together, this study not only elucidates the evolutionary processes driving the emergence and development of MLS resistance but also highlights the potential of using non-coding genomic allele data to predict antibiotic resistance phenotypes. IMPORTANCE Antibiotic resistance (AR) poses a global health threat as the efficacy of available antibiotics has rapidly eroded due to the widespread transmission of AR genes. Using Erm-dependent MLS resistance as a model, this study highlights the significance of non-coding genomic allelic variations. Through a comprehensive analysis of upstream regulatory elements within the erm family, we elucidated the evolutionary emergence and development of AR mechanisms. Leveraging population-wide machine learning (ML)-based genomic analysis, we transformed substantial non-random allelic variations into discernible clusters of elements, enabling precise prediction of MLS phenotypes from non-coding regions. These findings offer deeper insight into AR evolution and demonstrate the potential of harnessing non-coding genomic allele data for accurately predicting AR phenotypes.

  PublisherDOI

• Staphylococcal exoribonuclease YhaM destabilizes ribosomes by targeting the mRNA of a hibernation factor

  Nucleic Acids Research · 2024-07-09 · 4 citations

  articleOpen accessSenior author

  The hibernation-promoting factor (Hpf) in Staphylococcus aureus binds to 70S ribosomes and induces the formation of the 100S complex (70S dimer), leading to translational avoidance and occlusion of ribosomes from RNase R-mediated degradation. Here, we show that the 3'-5' exoribonuclease YhaM plays a previously unrecognized role in modulating ribosome stability. Unlike RNase R, which directly degrades the 16S rRNA of ribosomes in S. aureus cells lacking Hpf, YhaM destabilizes ribosomes by indirectly degrading the 3'-hpf mRNA that carries an intrinsic terminator. YhaM adopts an active hexameric assembly and robustly cleaves ssRNA in a manganese-dependent manner. In vivo, YhaM appears to be a low-processive enzyme, trimming the hpf mRNA by only 1 nucleotide. Deletion of yhaM delays cell growth. These findings substantiate the physiological significance of this cryptic enzyme and the protective role of Hpf in ribosome integrity, providing a mechanistic understanding of bacterial ribosome turnover.

  PublisherOA PDFDOI

• Epitranscriptional m6A modification of rRNA negatively impacts translation and host colonization in Staphylococcus aureus

  PLoS Pathogens · 2024-01-22 · 12 citations

  articleOpen accessSenior authorCorresponding

  Macrolides, lincosamides, and streptogramin B (MLS) are structurally distinct molecules that are among the safest antibiotics for prophylactic use and for the treatment of bacterial infections. The family of erythromycin resistance methyltransferases (Erm) invariantly install either one or two methyl groups onto the N6,6-adenosine of 2058 nucleotide (m6A2058) of the bacterial 23S rRNA, leading to bacterial cross-resistance to all MLS antibiotics. Despite extensive structural studies on the mechanism of Erm-mediated MLS resistance, how the m6A epitranscriptomic mark affects ribosome function and bacterial physiology is not well understood. Here, we show that Staphylococcus aureus cells harboring m6A2058 ribosomes are outcompeted by cells carrying unmodified ribosomes during infections and are severely impaired in colonization in the absence of an unmodified counterpart. The competitive advantage of m6A2058 ribosomes is manifested only upon antibiotic challenge. Using ribosome profiling (Ribo-Seq) and a dual-fluorescence reporter to measure ribosome occupancy and translational fidelity, we found that specific genes involved in host interactions, metabolism, and information processing are disproportionally deregulated in mRNA translation. This dysregulation is linked to a substantial reduction in translational capacity and fidelity in m6A2058 ribosomes. These findings point to a general "inefficient translation" mechanism of trade-offs associated with multidrug-resistant ribosomes.

  PublisherDOI

• The Identity of the Constriction Region of the Ribosomal Exit Tunnel Is Important to Maintain Gene Expression in Escherichia coli

  Microbiology Spectrum · 2022-03-21 · 1 citations

  articleOpen access

  All newly synthesized proteins must pass through a channel in the ribosome named the exit tunnel before emerging into the cytoplasm, membrane, and other compartments. The structural characteristics of the tunnel could govern protein folding and gene expression in a species-specific manner but how the identity of tunnel elements influences gene expression is less well-understood. Our global transcriptomics and translatome profiling demonstrate that a single substitution in a non-conserved amino acid of the E. coli tunnel protein uL22 has a profound impact on catabolism, cellular signaling, and acid resistance systems. Consequently, cells bearing the uL22 mutant ribosomes had an increased ability to survive acidic conditions and form biofilms. This work reveals a previously unrecognized link between tunnel identity and bacterial stress adaptation involving pH response and biofilm formation.

  PublisherDOI

• Bidirectional sequestration between a bacterial hibernation factor and a glutamate metabolizing protein

  Proceedings of the National Academy of Sciences · 2022-09-19 · 10 citations

  articleOpen accessSenior author

  Bacterial hibernating 100S ribosomes (the 70S dimers) are excluded from translation and are protected from ribonucleolytic degradation, thereby promoting long-term viability and increased regrowth. No extraribosomal target of any hibernation factor has been reported. Here, we discovered a previously unrecognized binding partner (YwlG) of hibernation-promoting factor (HPF) in the human pathogen Staphylococcus aureus . YwlG is an uncharacterized virulence factor in S. aureus . We show that the HPF–YwlG interaction is direct, independent of ribosome binding, and functionally linked to cold adaptation and glucose metabolism. Consistent with the distant resemblance of YwlG to the hexameric structures of nicotinamide adenine dinucleotide (NAD)–specific glutamate dehydrogenases (GDHs), YwlG overexpression can compensate for a loss of cellular GDH activity. The reduced abundance of 100S complexes and the suppression of YwlG-dependent GDH activity provide evidence for a two-way sequestration between YwlG and HPF. These findings reveal an unexpected layer of regulation linking the biogenesis of 100S ribosomes to glutamate metabolism.

  PublisherDOI

• The mTORC1-SLC4A7 axis stimulates bicarbonate import to enhance de novo nucleotide synthesis

  Molecular Cell · 2022 · 40 citations

  • Biology
  • Cell biology
  • Biochemistry
  PublisherOA PDFDOI

Recent grants

• Evolution and consequences of multidrug resistant ribosome

  NIH · $2.3M · 2020–2026

• NIH Grant R00GM094212

  NIH · $725k · 2015

• Regulation and function of bacterial hibernating 100S ribosome

  NIH · $3.2M · 2017–2026

Frequent coauthors

• Amy O. Charkowski

  Colorado State University

  8 shared

• Kathryn E. Shields

  Saint Louis University

  6 shared

• Arnab Basu

  6 shared

• Harris D. Bernstein

  National Institute of Diabetes and Digestive and Kidney Diseases

  6 shared

• David W. Gohara

  Saint Louis University

  5 shared

• Jeri D. Barak

  University of Wisconsin–Madison

  4 shared

• Amber R. Davis

  Saint Louis University

  4 shared

• Ching-Hong Yang

  University of Wisconsin–Milwaukee

  4 shared

Labs

• Yap LaboratoryPI

Education

• Ph.D., Plant Pathology

  University of Wisconsin Madison

  2006