CITATION: Roberts MC. 1997. Mechanisms of antibiotic resistance in oral bacteria. APUA Newsletter 15(2): 1, 4-6.

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Mechanisms of antibiotic resistance in oral bacteria
Marilyn C Roberts
School of Public Health and Community Medicine, University of Washington, Seattle, Washington, USA

The upper respiratory tract, including the nose, oral cavity, nasopharynx, and pharynx harbors a wide range of Gram-positive, Gram-negative cell-wall-free aerobic and anaerobic bacteria.

Oral microflora populations are not static. They change in response to the age, hormonal status, diet, and overall health of an individual. In addition, new and different microbes are ingested or inhaled daily. The exact composition of species will vary among individuals and, over time, in the same individual. An estimated 300 or more different species may be cultured from periodontal pockets alone, and up to 100 species may be recovered from a single site (1).

Such bacterial microcosms provide an excellent opportunity for the transfer of antibiotic resistance genes. The normal microbial flora of the human body act as a reservoir for such resistance traits (2). Gene exchange has been demonstrated among oral and urogenital species of bacteria, and between divergent oral bacteria under laboratory conditions. Prophylactic use of antibiotics before many dental procedures and for periodontal disease or oral abscess-infections that have not been shown to require antibiotic therapy (3)-contribute to the resistance reservoir. The b-lactams, tetracyclines, and metronidazole are the most commonly recommended and prescribed. Macrolides, clindamycin, and fluoroquinolones are rarely used, while aminoglycosides are normally not recommended.

Resistance to beta-lactam antibiotics
Enzymatic. Resistance to the beta-lactam antibiotics is most often due to an enzyme, beta-lactamase, which hydrolyses amides, amidines, and other carbon and nitrogen bonds, inactivating the antibiotic. More than 190 unique beta-lactamases have been identified in Gram-positive and Gram-negative bacteria from the oral tract (Table 1) (4).

The first beta-lactamase in common oral bacteria was described on a plasmid in
H. influenzae in the early 1970's. It carried the TEM-1 beta-lactamase first described in E. coli. The TEM-1 enzymes have been found in H. parainfluenzae and H. paraphrohaemolyticus and may be found in commensal Haemophilus species (2). The TEM-1 beta-lactamase is usually associated with large conjugative plasmids that are specific for the genus Haemophilus (2), which can also carry other genes for resistance to chloramphenicol, aminoglycosides and tetracycline.

At about the same time,
Neisseria gonorrhoeae acquired TEM-1 beta-lactamase on small plasmids (2) which can be mobilized to other strains by transfer plasmids in the strains. They are closely related to a susceptible H. parainfluenzae plasmid and small TEM beta-lactamase plasmids from H. ducreyi and H. parainfluenzae. (5). Some have hypothesized that H. parainfluenzae may be the most likely ancestral source for these related TEM beta-lactamase plasmids (5). Plasmids from this group have been reported periodically in N. meningitidis although no natural isolates have survived for independent testing. However, the small N. gonorrhoeae beta-lactamase plasmids can be transferred and maintained in N. meningitidis by conjugation under laboratory conditions.

TEM beta-lactamase has also been reported in a variety of commensal
Neisseria species (Table 1), usually found on small plasmids genetically related to the E. coli RSF1010 plasmid rather than the gonococcal plasmid (5). Similar plasmids have been found in Eikenella corrodens. These RSF1010-like plasmids may carry genes conferring resistance to sulfonamide or streptomycin singly or in combination (5). Larger plasmids from multi-resistant N. sicca have also been described, coding for resistance to tetracycline, a variety of aminoglycosides, and to the TEM beta-lactamases (5). Isolates of multi-resistant Moraxella (Branhamella) catarrhalis, initially reported to CDC for confirmation, were later identified as commensal Neisseria species.

A second beta-lactamase ROB has been described in
H. influenzae on a small plasmid that is virtually identical to ROB-bearing plasmids found in a number of strictly animal bacterial pathogens, including Actinobacillus and Pasteurella species.

More recently, strict anaerobic Gram-negative bacteria, including
Bacteroides forsythus, Fusobacterium nucleatum, Prevotella species, Porphyromonas asaccharolytica, and Veillonella species, have been shown to carry genes for b-lactamases. Only some of the enzymes have been characterized (Table 1), and the genetic location (plasmid vs. chromosome) has generally not been determined.

Non-enzymatic. Resistance to penicillin in naturally transformable bacteria (
Haemophilus, Neisseria, Streptococcus) can be due to replacement of parts of the genes encoding for penicillin-binding proteins (PBP), the targets of penicillin, with corresponding regions from more resistant species (6). This mechanism of resistance is less common than is resistance caused by beta-lactamases. For N. meningitidis, these more resistant regions of the PBP genes are closely related to the genes of commensal N. flavescens and N. cinera (6). One of the PBP genes, penA, has been shown to be very diverse, with 30 different mosaic genes found among 78 different isolates examined. The mosaic PBPs in S. pneumoniae have regions from S. mitis as well as from unknown streptococcal species (6).

Another non-enzymatic resistance mechanism, found in methicillin-resistant
S. aureus, is the mecA gene, a genetic determinant which codes for an additional low-affinity penicillin-binding protein, PBP2a (7), and lies on a 30 to 40 kb DNA element that confers an intrinsic resistance to beta-lactams (8). Among 15 different species of Staphylococcus screened for the mecA gene, 150 isolates of Staph. sciuri hybridized to the gene(9). Because not all Staph. sciuri are penicillin resistant, the Staph. sciuri mecA homolog may perform a normal physiological function in its natural host unrelated to beta-lactam resistance (9).

Tetracycline resistance
Eighteen distinguishable determinants for tetracycline resistance have been described that specify primarily two mechanisms of resistance: efflux and protection of ribosomes (10). The distribution of the different Tet determinants varies widely, related in part to the ease of transfer of particular Tet determinants between various isolates and genera (10). The Tet B gene has the widest host range among the Gram-negative efflux genes and has been identified in a number of oral species (Table 2)(10). Both
A.actinomycetemcomitans and T. denticola have been associated with periodontal disease. The TetB determinant is found on conjugative plasmids in Actinobacillus and Haemophilus species (4,10). The plasmid carrying tet (B) from A.actinomycetemcomitans was transferable to H. influenzae (11). The TetB determinant was not mobile in the small number of Moraxella and Treponema isolates examined (12).

Recently, we found the Gram-positive efflux-mediated genes [
tet (K) and tet (L)] in a few oral Gram-negative bacteria (Table 2). Haemophilus aphrophilus, isolated from periodontal patients in the 1990s, carried the tet (K) gene (10). A few isolates of V. parvula have been found that carry tet (L) or tet (Q); however, most of the isolates examined carry the tet (M) gene. Oral streptococci may carry multiple different tet genes, and tet (M), tet (Q), tet (K), and tet (L) have all been found in streptococci, singly or in combination (Table 3). Recently, other ribosomal protection genes [tet (U), tet (S) and tet (T)] have been found in enterococci (13,14,15). TetS has been found in S.milleri and tetracycline-resistant streptococci have been isolated that do not carry any of the known tet genes (15). Tet (M), which produces a ribosome-associated protein, is widely distributed in both Gram-positive and Gram-negative genera (Tables 2 and 3).

tet (Q) ribosomal protection gene was first found in colonic Bacteroides and has usually been found in Gram-negative anaerobic species that are related to Bacteroides, such as Prevotella (Table 2). A few isolates of V. parvula have been found to carry tet (Q); however, most of the isolates characterized carry tet (M) (10). Oral Mitsuokella and Capnocytophaga also carry tet (Q).

Other resistance mechanisms
Metronidazole resistance has been reported in oral bacteria, but the genetic basis is not known. In colonic Bacteroides, four genes, nimA, nimB, nimC and nimD, have been described and sequenced. They are located on either the chromosome or a variety of plasmids, confering a range of resistance. The nim genes likely code for a 5-nitroimidazole reductase that enzymatically reduces 5-nitroimidazole to a 5-amino derivative (16).

Enzymes that acetylate, phosphorylate, or adenylate aminoglycosides have been characterized in
S. pneumoniae, other streptococci, staphylococci, and, more recently, commensal Neisseria and Haemophilus species (3,5). An isolate of C. ochraceus has been found that is resistant to aminoglycosides, chloramphenicol, and tetracycline.

Early isolates of erythromycin-resistant
S. pneumoniae carried the Erm B class of rRNA methylases, which modifies a single adenine residue in the 23S RNA conferring resistance to macrolides, lincosamides and streptogramin B. We have identified rRNA methylases in A. actinomycetemcomitans and Campylobacter rectus. In both species, the rRNA methylases are associated with conjugative elements that can be transferred to Enterococcus faecalis and from A. actinomycetemcomitans to H. influenzae (11). Many other oral bacteria have been reported to be resistant to erythromycin or clindamycin.

Bacteria making up the oral flora are reservoirs of important antibiotc resistance traits. Their emergence reflects the overuse and misuse of antibiotics and their potential for transfer of these traits to other more pathogenic species.


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